m 

M^ 

tm 

WMMs'h 


If ■'■'•''(  lit'- ■  '-'  ' 


mfi'''^ 


7dcan6p  opmcd and  dosed  \ 


-24a. 


The  Oxford  Medicine 


BY  VARIOUS  AUTHORS 


"^     EDITED    BY 


HENRY  A.  CHRISTIAN,  A.M.,  M.D. 

Hersey  Professor  of  the  Theory  and  Practice  of  Physic,  Harvard  University 

Physician-in-Chief  to  the  Peter  Bent  Brigham  Hospital, 

Boston,  Mass. 


OXFORD  UNIVERSITY  PRESS 

AMERICAN    BRANCH,    35    WEST    JIND    STREET,    NEW  YORK 
LONDON     •     TORONTO     •     MELBOURNE     ■     BOMBAY 


\>)B  \QD 

Copyright,  1920 

BY   THE 

OXFORD  UNIVERSITY  PRESS 
American  Branch 

Supplemented  to  ig26 


Priuted  in  U.  S.  A. 


CHAPTER  X 
VITAMINS  AND  VITAAIIN  DEFICIENCIES 

By  TOM  D.  SPIES  and  HUGH  R.  BUTT 

Table  of  Contents 

Introduction 437 

Vitamins  A 439 

Chemistry 440 

Physiology 442 

Food  Sources 445 

Experimental  Pathological  Physiology 446 

Human  Requirements 448 

Deficiency  of  Vitamin  A  in  Man 448 

Methods  for  Measuring  Deficiency  of  Vitamin  A  .  452 

Toxicity 452 

Diagnosis  of  Vitamin  A  Deficiency 452 

Differential  Diagnosis 452 

Treatment  of  Vitamin  A  Deficiency 452 

Bibliography 452 

Vitamins   D 452 

Chemistry 452 

Physiology 452 

Food  Sources 452 

Experimental  Pathological  Physiology 452 

Human    Requirements 452 

Methods  for  Measuring  Deficiency  of  Vitamin  D  .  452 

Toxicity 452 

Diagnosis  of  Vitamin  D  Deficiency 452 

Treatment  of  Vitamin  D  Deficiency 452 

Bibliography         452 

Vitamin  E 452 

Chemistry 452 

Physiology  and  Pathology 452 

Clinical  Use  of  Vitamin  E 452 

Bibliography 452 

Vitamins  K 452 

Chemistry 452 

Physiology 452 

Sources  452 

Experimental  Pathological  Physiology 452 

COPYRIGHT  1948  BY  THE  OXFORD  UNIVERSITY  PRESS,  INC. 

435 


^) 

2) 

3) 

3) 

133) 

5) 

5) 

6) 

9) 

11) 

13) 

14) 

14) 

16) 

19) 
135) 
") 
22) 

23) 

24) 

137) 

26) 

26) 

28) 

30) 

30) 


436  MTAAIINS  AND  VITAMIN  DEFICIENCY 

Human  Requirements 452 

Deficienc\'  of  \^itannn  K  in  Alan  452 

Deficienc\'  of  Prothrombin  among  New  Born  Infants  452 

Methods  for  Measuring  Deficienc}'  of  Vitamin  K  45 ^ 

Toxicity  452 

Diagnosis  of  \'itamin  K  Deficiencx' 452 

Treatment  of  Vitamin  K  Deficienc\' 452 

Bibhographv 452 

Vitamin  C 452 

Historv 452 

Cheniistr\'   and   Phwsiology 452 

Pathological  Physiology 452 

Symptomatology 452 

Infantile   Scurvy 452 

Adult  Scurvy 452 

Diagnosis  452 

Prevention  and  Treatment 452 

Bibliographv  452 

Vitamin  Bi   (Thiamine) 452 

History 452 

Chemistry  and  Physiology 452 

Pathological   Physiology 452 

Symptomatologx'  452 

Diagnosis  452 

Prevention  and  Treatment 452 

Toxicity 452 

Bibliography  452 

Nicotinic  Acid  Amide : 452 

History  452 

Chemistry  and  Physiology 452 

Relationship  between  Co-enzvme  I  and  II  and  Nico- 
tinic Acid  Amide  Deficiency  45  2 
Absorption,  Distribution,   Excretion  and  Effects  452 

Pigment  Metabolism 45 

Pathological  Physiology  .  452 

Symptomatology 45 

Diagnosis 45 

Prevention  and  Treatment 452 

Toxicity  452 

Bibliography  452 

Riboflavin 452 

History 452 

Chemistry  and  Physiology 452 

Pathological   Physiology 452 

Symptomatology 452 

Diagnosis 452 

\'oi..  I.  948 


32) 

32) 
35) 
39) 
40) 
40) 

43) 
138) 

47) 

47) 

47) 

51) 

58) 

59) 

60) 

61) 

63) 

'14) 

66) 

66) 

67) 

70 

70 

75) 

77) 

79) 

145) 

80) 

80) 

80) 

80 
83) 
85) 
86) 

87) 
89) 
90 
100) 

147) 

lOl) 
lOl) 

lOI  ) 

104) 
106) 
109) 


INTRODUCTION  437 

Prevention  ;iiul  Trenrnicnr 452(111) 

Toxicirx  452(113) 

Bibliography 452(148) 

Folic    Acid         452(114^ 

History  452(114) 

Chemistry  and  Physiology 452(115) 

Pathological   Physiology  452(119) 

Symptomatology 452(123) 

Diagnosis  452(123) 

Treatment 45^(^-5' 

Toxicity  452(133) 

Bibliography  452(150) 

INTRODUCTION 

The  advances  in  nutrition  have  received  a  great  deal  of  pubhcity  in 
the  lay  and  scientific  press  during  the  last  few  years  probably  because 
of  the  most  unusual  and  dramatic  circumstances  of  the  discovery  of  the 
vitamins.  Many  of  the  reports  are  correct,  but  others  are  not  reliable. 
Consumers  are  being  subjected  to  a  ballyhoo  that  brings  to  mind  stories 
of  the  Indian  tonic  days.  \"itamins  have  been  reported  to  cure  almost 
every  illness  of  man  or  beast.  The  modern  science  of  nutrition,  although 
it  may  seem  to  some  to  promise  miracles,  offers  no  elixir  of  life  and  no 
panaceas.  It  does  offer  specific  therapy  for  vitamin  deficiency  diseases 
and  holds  promise  for  far-reaching  results  in  the  near  future.  Certain  it  is 
that  vitamins  are  necessary  for  tlie  health  and  vigor  of  the  higher  forms 
of  life;  yet  it  is  equally  certain  that  they  are  of  no  value  where  no  defi- 
ciency exists.  They  are  organic  food  substances  which,  in  small  quanti- 
ties, are  necessary  for  maintaining  proper  growth  and  continued  health  of 
the  human  body.  The  amounts  required  are  so  small  that  it  is  almost 
certain  that  they  act  as  catalysts  or  help  to  form  such  in  the  human  body. 
They  are  important  in  the  biochemical  systems  of  the  body  which  gov- 
ern the  oxidation  of  carbohydrates,  proteins  and  fats.  They  have  func- 
tional relationships  with  minerals  and  perhaps  with  all  other  essential 
elements  of  the  dietary. 

Already  vitamins  are  used  widely  in  medicine.  Bv  prescribing  them 
judiciously  many  physicians  apply  them  successfully  in  their  practice 
of  medicine.  Others  use  them  injudiciously  and  with  no  success.  Some 
refuse  to  use  them  at  all.  Still  others  prescribe  them  for  appearance 
sake.  The  physician  has  been  justifiabK'  sceptical  toward  the  introduc- 
tion of  each  new  vitamin  as  a  therapeutic  agent,  but  sometimes  he  has  let 
his  doubts  give  way  to  an  attitude  of  complete  confidence,  a  confidence 

\^OL.  I.  948 


438  VITAMINS  AND  VITAMIN  DEFICIENCY 

not  always  warranted.  The  rapidity  with  which  these  advances  in 
nutrition  have  come,  which  is  shown  in  Fig.  i,  is  almost  unparalleled  in 
medicine,  and  there  is  great  need  for  investigation  by  conservative  phy- 
sicians, who  will  test  each  new  material  and  appraise  its  effect  on  human 
beings  under  controlled  conditions. 

That  the  present  state  of  our  knowledge  of  nutrition  frequently  is 
confusing  and  often  contradictory  is  due  largely  to  inadequately  con- 

f  TH  I  AM  IN        ■♦ 


NICOTINIC      ACID 


VITAMIN      E    •¥ 


V  1  TA  rs4  1  N      A 


0    THIRAPEUriCAILY     FOft  4     ,|  f 


/^/^r     SOlU&Lf     -+  *-    l^Ar£/3    SOLU&L£ 


VITAM  INS 


Fig.    I.    Diagram   showing   important   vitamins   with   important   dates   in   their   de- 
velopment. 

trolled  clinical  investigations  in  a  field  that  once  was  considered  very 
simple.  Clinical  experimentation  with  the  vitamins  must  continue,  and 
at  the  same  time  we  must  exercise  great  scepticism  in  regard  to  what 
may  be  attributed  to  their  therapeutic  effect. 

As  physicians  we  abhor  "polypharmacy",  yet  there  is  a  logical  basis 
for  inchiding  sufficient  amounts  of  a  variety  of  vitamins  in  a  single 
therapeutic  preparation.  The  vitamins  tend  to  occur  together  in  nature, 

Vol.  I.  948 


VITAMINS  A  439 

and  the  practice  of  medicine  will  be  enriched  by  a  full  realization  that 
the  deficiency  diseases  occur  as  complexities  rather  than  as  single  entities 
and  must  be  treated  as  such.  Convalescence  from  nutritional  deficiency 
diseases  often  is  shortened  greatly  by  administering  vitamins  in  suitable 
mixtures  rather  than  by  administering  a  single  vitamin. 

The  use  of  vitamins  in  medicine  illustrates  vividly  the  immense  surge 
that  can  be  given  to  the  biological  or  chemical  field  when  it  progresses 
to  the  point  where  it  has  important  clinical  application.  Because  of  its 
crreat  scientific  and  therapeutic  value  research  on  the  vitamins  has  been 
of  intense  interest  to  the  authors  of  this  chapter.  In  writing  these  sections 
on  the  vitamins  we  have  looked  backward  over  a  large  experience  and 
have  eliminated  all  but  those  facts  that  seem  essential  to  the  physician, 
who  would  achieve  his  goal  of  full  rehabilitation  of  every  patient  with 
nutritional  deficiency  diseases.  It  is  our  hope  that  most  of  the  material  in 
this  chapter  will  be  of  immediate  value  in  the  practice  of  medicine  and 
that  much  of  it  will  interest  the  biochemist,  the  biologist,  the  physiol- 
os^ist,  the  pharmacologist  and  the  student  of  nutrition. 

In  the  following  pages  we  will  discuss  the  vitamins,  in  which  the 
practicing  physician  will  be  particularly  interested,  the  four  fat-soluble 
vitamins  A,  D,  E,  and  K,  the  four  water-soluble  vitamins,  C,  (ascorbic 
acid)  and  B  (thiamin,  nicotinic  acid  amide  and  riboflavin)  and  folic 
acid.  Each  of  the  sections  has  been  written  as  a  separate  unit  concerned 
only  with  one  of  these  vitamins  and  its  corresponding  disease.  Theories 
have  been  discussed  as  little  as  possible,  and  all  the  material  is  presented 
with  as  little  prejudice  as  strong  personal  opinions  allow. 


VITAMINS  A 

Epidemics  of  xerophthalmia  and  keratomalacia  had  been  reported  in 
the  medical  literature  some  thirty  or  forty  years  before  the  compound 
termed  "fat-soluble  A"  was  recognized.  These  conditions  were  ob- 
served to  appear  chiefly  among  children;  even  at  an  early  date  a  dietary 
origin  was  suspected,  and  cod  liver  oil  was  noted  to  be  effective  in  ameli- 
orating the  conditions.  These  clinical  obervations  then  were  followed 
by  many  experimental  studies,  results  of  which  suggested  strongly  that 
there  was  present  in  certain  foodstuffs  a  fat-soluble  compound  which 
was  essential  for  normal  growth.  It  was  not,  however,  until  191 3  that 
McCollum  and  Davis  reported  the  occurrence  in  certain  foods  of  a  com- 
pound termed  "fat-soluble  A".    In  1922  it  was  shown  clearly  that  the 

Vol.  I.  948 


440  MTAMINS  AND  VITAMIN  DEFICIENCY 

anti-ophthalmic  factor  in  cod  liver  oil  could  be  destroyed  by  oxidation 
without  destruction  of  the  anti-rachitic  factor. 

In  these  early  experiments  it  was  noted  that  swelling  of  the  lids  of 
one  eye  or  both  eyes  developed  in  animals,  rats,  subsisting  on  a  diet  de- 
ficient in  vitamin  A,  after  which  there  commonly  developed  an  inflamed 
and  catarrhal  condition  of  the  conjunctiva  with  a  bloody  or  purulent 
discharge.  It  was  noted  that,  if  this  ophthalmic  condition  \\'as  not  treated 
and  the  animals  continued  to  live,  the  cornea  became  affected,  and  blind- 
ness resulted.  Significantly  it  \\as  noted  also  that  ^^'ithout  any  local 
treatment,  if  the  ophthalmic  disease  was  not  too  far  advanced,  the  symp- 
toms disappeared  rapidly  after  the  ingestion  of  food  containing  an  ade- 
quate amount  of  vitamin  A.  This  relationship  of  diseases  of  the  eye  to 
dietary  deficiency  also  was  demonstrated  experimentallv  in  other  species 
as  well  as  rats,  and  it  was  sho\Mi  also  in  these  studies  that  certain  diseases 
of  the  eve  of  man  might  be  the  result  of  deficiency  of  \'itamin  A.  Soon  it 
was  reported  that  xerophthalmia  in  man  could  be  prevented  or  cured  by 
the  administration  of  food  rich  in  the  A  vitamin^  ^ 


CHI:.\IISIR^ 

Although  between  lyi^  and  1915  McCoIlum  and  Davis  and  Osborne 
and  .Mendel  had  ascertained  the  presence  of  "fat-soluble  A"  in  cod  liver 
oil  and  in  butter,  it  was  not  until  1933  that  Karrer  synthesized  perhydro- 
vitamin  A.  The  structural  formula  of  vitamin  A  is  shown  in  Fig.  2. 

.C  H     H  CH3   H      H     H  CHj   H      H 

^    ^/    \         I        I      \        I        I        I     \         I       I 
HzC  C-C=C-C=C-C=C-C=C-C-OH 

I  I  H 

HzC  C— CHj 

C 
Ha 

Fig.  :.      1  lie  structural  lormula  of  \  itaniin  Ai. 

This  primary  alcoholic  structure  of  vitamin  A  is  important  in  that  it 
allows  for  esterification  and,  therefore,  the  formation  of  compounds  of 
vitamin  A  with  protein,  bile  acids  and  fatty  acids.  These  compounds  of 
vitamin  A  are  decomposed  with  liberation  of  the  vitamin  b\'  such  hydro- 
lytic  processes  as  occur  in  saponification;  the  vitamin  is  an  alcohol;  hence, 
it  is  not  itself  saponifiable.  N^itamin  A  is  a  hvdrogen  acceptor  probably 
because  of  its  unsaturated  form.  There  is  some  c\idence  to  indicate  that 

Vol..  1.  948 


VITAMINS  A:  CHEAIISTRY  441 

the  substance  rendilv  absorbs  oxygen  in  solution  and  is  markedly  pro- 
oxygenic  when  undergoing  oxidation.  However,  highly  oxidized  vita- 
min A  has  no  biological  activity.  A^itamin  A  is  very  sensitive  to  oxidation 
and  auto-oxidizes  readily.  It  is  heat-stable  but  of  course  insoluble  in 
water.  Vitamin  A  does  not  show  any  absorption  band  in  the  visible  re- 
gion of  the  spectrum,  but  it  does  show  a  rather  broad  absorptive  ret^ion  in 
the  ultraviolet.  These  properties  form  the  basis  for  the  spectrophoto- 
metric  method  for  the  quantitative  estimation  of  vitamin  A. 

On  the  basis  of  recent  reports  it  appears  that  there  exists,  in  addition 
to  vitamin  A  compound  designated  as  "vitamin  A2".  In  chemical  struc- 
ture vitamin  Ai  is  related  very  closely  to  vitamin  A2,  and  biologically  the 
activity  is  the  same.  Rather  extensive  investigations  of  the  distribution  of 
these  two  forms  of  vitamin  A  have  led  definitely  to  the  conclusion  that 
vitamin  Ai  predominates  in  the  tissues  of  salt-water  fishes  and  that  vita- 
min A-2  predominates  in  the  tissues  of  fresh-water  fishes.  The  absence  of 
vitamin  A2  from  the  liver  of  mammals  and  other  land  animals  probably 
can  be  explained  by  the  absence  of  vitamin  A2  from  their  food.  Vitamin 
A2  has  not  been  isolated  in  pure  crystalline  form.  There  is  no  evidence 
that  vitamin  A2  plays  any  significant  role  in  mammalian  nutrition. 

CHj       CHj  CHz        CH 

y^  CH,  CH3  CH3  CH5 

H2C  C  CH=CH-C-CH-CH=CH-C=CH-CH=CH-CH=C-CH=CH-CH=C-CH=CH-C^         \h. 


HjC  CCHi 


HiCC  CHa 


CH, 


CH, 


Fig.  3.     The  structunil  foniiul:!  for  beta  carotene. 


There  are  many  reasons  for  assuming  tliat  some  other  types  of  vita- 
min A  exist.  Recently*'  a  geometric  isomer  of  vitamin  At  has  been  re- 
ported, which  has  biological  potency  nearly  the  same  in  kind  and  magni- 
tude as  that  of  vitamin  Ai. 

Most  of  the  vitamin  A  available  to  man  in  his  diet  is  in  the  form  of 
its  precursors,  the  yellow  and  red  carotenoid  pigments,  provitamins.  For 
this  reason  the  chemical  properties  of  these  compounds  are  rather  impor- 
tant. There  are  nine  different  naturally  occurring;-  compounds  known  as 
"provitamins  A".  These  are  alpha,  beta  and  gamma  carotene,  cryptoxan- 
thene,  echinenone,  myxoxanthin,  leprotene,  aphanin  and  aphanicin. 
These  provitamins  A  belong  chemically  to  a  special  class  called  "caro- 
tenoids".  They  are  extremely  sensitive  to  oxidation,  auto-oxidation  and 

^^oL.  I.  948 


442  VITAMINS  AND  VITAMIN  DEFICIENCY 

light  but  are  stable  to  heat.  Little  is  known  of  the  biogenesis  of  provita- 
mins A,  and  none  have  yet  been  synthesized.  Of  this  large  group  of  pig- 
ments, however,  the  beta  form  yields  two  molecules  of  the  vitamin, 
whereas  each  of  the  other  produces  only  one  molecule.  This  can 
be  seen  easily  in  the  formula  of  beta  carotene  shown  in  Fig.  3.  Theo- 
retically, if  the  splitting  ocurrs  in  the  middle,  one  molecule  may  give  rise 
to  two  molecules  of  vitamin  A.  It  was  the  ingenious  research  of  Karrer 
which  first  proved  that  beta  carotene  contains  two  beta-ionone  rings.  It 
was  shown  also  by  these  investigations  that  the  beta-ionone  ring  is  an 
essential  component  of  the  molecular  structure  of  vitamin  A.  All  the 
carotenoids  that  yield  vitamin  A  exhibit  characteristic  absorption  bands 
in  the  visible  region  of  the  spectrum. 

Although  its  exact  function  is  unknown,  carotene  obviously  is  of 
great  importance  in  the  physiological  processes  of  plants.  It  constitutes 
a  family  associated  closely  with  chlorophyll,  although  it  is  not  lost  when 
the  chlorophyll  disappears  at  the  time  of  the  yellowing  of  leaves.  How- 
ever, it  is  destroyed  completely  in  dry  dead  leaves.  Rapid  drying  by  arti- 
ficial heat  also  destroys  the  provitamin.  All  these  facts  are  important 
because  carotene  of  green  leaves  is  brought  indirectly  into  human  nutri- 
tion through  milk  and  eggs. 

The  conversion  of  the  precursors  into  vitamin  A  apparently  takes 
place  in  the  animal  liver,  and  it  is  of  clinical  significance  that  this  trans- 
formation is  retarded  in  the  presence  of  phosphorus  poisoning  and  in 
other  forms  of  hepatic  injury.  It  is  thought  that  the  conversion  of  caro- 
tene into  vitamin  A  takes  place  by  the  aid  of  an  enzyme  in  the  liver  called 
"carotenase".  Although  there  is  much  evidence  that  the  liver  is  the  site 
of  conversion,  there  is  also  some  evidence  that  the  human  pancreas  is 
involved^ 

Physiology 

The  absorption  and  utilization  of  vitamin  A  and  carotene  depend  on 
many  factors,  and  because  of  the  differences  in  absorption  and  utilization 
of  these  two  compounds,  both  of  them  must  be  described. 

Vitamin  A  is  a  fat-soluble  compound,  and  its  absorption  apparently 
is  facilitated  greatly  by  the  simultaneous  absorption  of  a  certain  amount 
of  fat.  Most  observers  believe  that  the  presence  of  bile  is  not  necessary 
for  proper  absorption  of  vitamin  A,  although  it  is  still  perhaps  good 
therapeutic  medicine  to  administer  bile  salts  with  concentrates  of  vitamin 
A  in  the  treatment  of  patients  who  have  obstruction  of  the  biliary  tract. 

Vol.  I.  948 


VITAiVIINS  A:  PHYSIOLOGY  443 

Absorption  of  the  vitamin  reaches  the  maximum  in  three  to  five  hours 
after  administration.  Although  there  apparently  is  some  loss  of  vitamin 
A  in  the  stool,  nothing  is  known  of  the  degree  of  destruction  of  vitamin 
A  in  the  gastrointestinal  tract  under  either  normal  or  pathological  con- 
ditions. Studies  on  a  person  who  had  a  fistula  of  the  thoracic  duct,  after 
the  administration  of  vitamin  A  or  carotene  by  mouth,  revealed  that  very 
little  of  the  carotene  passes  through  the  chylous  fluid,  whereas  nearly  all 
of  the  vitamin  A  can  be  recovered. 

Carotene  is  absorbed  less  readily  than  vitamin  A,  and  absorption 
itself  is  subject  to  several  more  hazards.  Proper  absorption  of  carotene 
requires  the  presence  of  bile  in  the  intestinal  tract  and  in  those  condi- 
tions, in  which  bile  is  completely  or  partially  excluded  from  the  intes- 
tinal tract,  or  in  those  instances,  in  which  bile  salts  of  good  quality  are 
excreted  poorly,  bile  must  be  given  as  a  supplement  to  insure  proper 
absorption.  Chronic  diarrhea,  pancreatic  dysfunction,  celiac  disease  or 
sprue  also  may  inhibit  the  absorption  of  carotene.  As  with  vitamin  A  a 
certain  amount  of  nomial  absorption  of  fat  also  seems  necessary  for  prop- 
er transportation  of  carotene  across  the  intestinal  wall.  It  has  been 
shown,  further,  that  mineral  oil  may  inhibit  seriously  the  absorption  of 
carotene.  For  this  reason  mineral  oil  should  not  be  given  soon  after 
meals.  Absorption  of  carotene  reaches  a  maximal  level  in  the  blood  in 
from  7  to  8  hours  after  administration,  and  the  amount  excreted  in  the 
feces  accounts  for  only  a  small  portion  of  the  unutilized  excess.  The  rest 
of  it  apparently  finds  other  channek  of  excretion  or  is  destroyed  in  the 
intestine  or  elsewhere.  The  kidney  apparently  does  not  play  any  part 
in  the  disposition  of  either  vitamin  A  or  its  precursors,  unless  the  body  is 
flooded  with  either  carotene  or  vitamin  A. 

The  capacity  ta  store  vitamin  A  varies  widely  among  different 
species  of  animals.  The  rat  has  a  remarkable  capacity  for  the  storage  of 
vitamin  A,  whereas  the  rabbit  and  guinea  pig  retain  little  of  this^sub- 
stance,  even  when  they  subsist  on  diets  rich  in  carotene.  In  these  par- 
ticular animals  a  large  part  of  the  total  content  of  vitamin  A  in  the 
body  is  present  in  the  liver,  although  small  amounts  appear  in  the  lungs 
and  kidneys.  However,  in  other  animals,  for  instance  fish,  greater 
amounts  of  vitamin  A  are  deposited  in  the  tunica  propria  of  the  mucosa 
of  the  intestine  than  in  the  liver. 

After  absorption  a  greater  portion  of  the  carotene  is  held  in  the  liver, 
where  it  gradually  disappears  from  the  Kupffer  cells  as  the  concentration 
of  vitamin  A  in  the  liver  increases.  Vitamin  A  itself  also  is  stored  prop- 
erly in  the  liver  in  the  Kupffer  cells.   In  human  beings  the  vitamin  A 

Vol.  I.  948 


444  VITAMINS  AND  VITAAIIN  DEFICIENCY 

content,  as  in  ;ill  ;inini;ils,  is  much  lower  in  the  Hver  ;it  birth  than  in  the 
liver  of  the  normal  adult,  irrespective  of  the  diet  of  the  mother.  The 
liver  probably  stores  about  95  per  cent,  of  the  vitamin  A  reserve  of  the 
body,  and  the  amount  stored  is,  as  a  rule,  smallest  in  the  liver  during 
childhood  and  increases  gradually  with  advance  in  age.  Examination  of 
the  livers  of  healthy  persons,  who  died  suddenly  from  accidental  causes, 
shows  them  to  average  331  U.S.P.  units  of  vitamin  A  per  gram  of  liver 
tissue. 

The  exact  mechanism  by  which  vitamin  A  is  called  forth  from  its 
reserve  stores  is  not  known,  but  from  several  sources  it  appears  that  the 
distribution  of  vitamin  A  in  the  circulating  blood  and  tissues  is  controlled 
in  part  by  the  nervous  system.  Evidence  has  been  presented  to  indicate 
the  existence  of  compounds  of  carotene  and  vitamin  A  with  protein, 
probably  albumin^ 

The  excretion  of  vitamin  A  appears  ta  be  highly  selective.  Neither 
vitamin  A  nor  the  provitamins  are  excreted  by  the  kidneys  unless  the 
organism  is  given  an  excessive  dose  of  these  substances.  It  has  been 
reported'',  how^ever,  that  in  human  urine  vitamin  A  is  absent  in  health 
but  present  in  association  with  some  pathological  conditions,  particularly 
pneumonia  and  chronic  nephritis. 

Using  fluorescence  microscopy  as  a  method  of  visualization  of 
vitamin  A  in  tissue  cells,  Steigmann  and  Popper"^  found  that  the  concen- 
tration of  vitamin  xA  in  the  human  liver  varies  even  under  normal  condi- 
tions. Among  young  infants  there  was  very  little  storage,  but  in  the 
embryo  of  about  five  months'  development  considerable  amounts  ap- 
peared, although  these  depots  of  vitamin  Mcre  reduced  later,  and  at  birth 
only  traces  were  distinct.  The  human  adrenal  tissue  and  lactating  breast 
tissue  were  found  to  be  rich  in  vitamin  A,  but  the  normal  tissues  of  the 
human  kidney,  brain,  cornea,  bronchi  and  urinary  tract  and  the  inactive 
breast  were  found  to  be  free  of  the  vitamin.  It  is  interesting  that  by  this 
method  it  was  found  that  the  retinas  of  rats,  dying  of  avitaminosis  A  with 
ulceration  of  the  cornea,  contained  vitamin  A". 

Only  extremely  small  quantities  of  these  compounds  can  be  found 
in  the  feces,  and  it  is  assumed  for  this  reason  that  unutilized  excesses  find 
other  channels  of  excretion  or  are  destroyed  in  the  intestine  or  elsewhere. 

Human  milk  contains  both  carotene  and  vitamin  A.  The  colostrum 
from  the  human  breast  has  from  two  to  three  times  the  biological  vitamin 
A  activity  of  earl\'  milk,  and  early  human  milk  has  from  five  to  ten 
times  the  biological  vitamin  A  activity  of  cow's  milk.  The  administra- 
tion of  \'itamin  A  in  large  doses  effectively  increases  the  vitamin  A 

Vol.  I.  948 


VITAMINS  A:  FOOD  SOURCES  445 

content  in  the  milk  of  the  hictating  huni;in  subject  in  the  same  way  as  in 
the  cow.  Doses  of  100,000  I.U.  daily  more  than  doubled  the  vitamin  A 
content  of  the  milk^". 

Food  Sources 

Vitamin  A  occurs  only  in  the  animal  organism.  Fish  liver  oils  are 
the  richest  source  of  vitamin  A.  Milk  (3  U.S.P.  units  per  gram),  butter 
(50  U.S.P.  units  per  gram)  and  tgg  yolks  all  are  rich  sources  of  vitamin 
A  of  animal  origin.  Margarine,  when  fortified  with  vitamin  A,  can  be 
substituted  for  butter  in  the  ordinary  diet",  ^^itamin  A  is  fairly  stable  to 
heat  and  not  appreciably  soluble  in  water;  it  is,  however,  destroyed  by 
oxidation,  and  foods  which  are  heated  for  long  periods  show  an  appre- 
ciable loss  of  vitamin  A  potency.  Since  the  vitamin  activity  is  not  affected 
at  the  temperature  of  boiling  water,  foods  cooked  in  this  manner  retam 
their  vitamin  A  potency.  Canned  foods  have  practically  the  same  vitamin 
A  value  as  the  corresponding  fresh  foods,  and  foods,  which  are  stored 
in  the  frozen  state,  maintain  their  maximal  vitamin  A  value,  but  dried 
and  dehydrated  foods  show  considerable  loss  of  vitamin  A  content. 

The  provitamins  A  occur  in  plants  and  generally  are  absent  from 
the  animal  organism.  There  are,  however,  a  few  exceptions.  Almost 
pure  betacarotene  has  been  found  in  the  corpus  luteum,  in  the  human 
placenta  and  in  the  adrenal  gland. 

Human  beings  depend  almost  entirely  on  provitamins  for  their 
source  of  vitamin  A.  Fortunately  vitamin  A  is  widespread  in  nature  in 
the  form  of  the  precursors,  the  yellow  and  red  carotenoid  pigments. 
These  pio-ments  are  found  in  the  plant  world,  being  distributed  from 
bacteria  to  garden  fruits  and  vegetables.  The  pigments  are  found  chiefly 
in  association  with  chlorophyll  and  in  the  green  leaves  of  plants,  but 
this  is  not  invariably  true,  since  carrots  and  sweet  potatoes  with  their 
yellow  color  also  are  rich  in  these  substances. 

Apparently  there  is  a  direct  parallel  between  greenness  (chlorophyll 
content)  and '  vitamin  A  activity  in  foods  of  plant  origin.  Among  the 
best  sources  of  vitamin  A  are  thin  green  leaves.  The  exact  relationship 
between  the  decree  of  greenness  and  vitamin  A  activity  is  not  under- 
stood, but  it  is  well  known  that  the  outer  green  leaves  of  iceberg  lettuce 
or  cabbage  are  much  more  potent  in  vitamin  A  than  are  the  inner  leaves. 
Peas,  gre^en  beans,  green  peppers,  parsley  stocks,  as^^aragus  and  green 
celery  all  are  known^to  have  a  high  content  of  vitamin  A.  Carrots,  sweet 
potatoes,  apricots,  yellow  peaches  and  yellow  tomatoes,  all  of  which 
Vol..  I.  948 


44^  VITAMINS  AND  VITAMIN  DEFICIENCY 

possess  a  yellowish  color,  are  rich  sources  of  vitamin  A.  Nuts  and  cereal 
trains,  with  the  exception  of  those  having  considerable  green  and  yellow 
color,  are  very  poor  sources  of  vitamin  A.  Yellow  corn  is  the  most 
important  vitamin  A  food  in  this  group. 


Experimental  Pathological  Physiology 

The  observations  of  \\V)lbach  and  Bessey,  Mellanby,  and  Moore  have 
established  growth  of  bone  and  the  nature  of  such  growth  as  important 
aspects  of  vitamin  A  deficiency,  ^^'olbach  and  Bessey  consider  that 
deficiency  of  vitamin  A  retards  bone  growth,  but  Mellanby,  on  the 
contrary,  believes  that  lack  of  the  vitamin  leads  to  increased  activity  of 
both  the  osteoblasts  and  osteoclasts  of  the  bone  with  proliferation  of 
cancellous  bone  at  the  expense  of  compact  bone^^'  ^^'  ^^^  Formerly  it  was 
believed  that  vitamin  A  produced  a  profound  effect  on  the  nervous  sys- 
tem. Wolbach  and  Bessey",  however,  have  shown  that  in  deficiency  of 
vitamin  A  in  rats  skeletal  growth  is  retarded  earlier  than  that  of  the  soft 
tissues  in  general,  including  growth  of  the  central  nervous  system,  and 
that  in  the  white  rat  at  least  the  nervous  manifestations  are  due  to  pres- 
sure effects  caused  by  relative  dvergrowth  of  the  central  nervous  system. 

EpitbeJ'nnu.  —  No  definite  changes  in  the  skin  of  experimental  animals 
have  been  described  as  following  deficiency  of  vitamin  A. 

Relationship  to  Infection.  — Since  McCollum  in  19 17  first  pointed 
out  that  severe  spontaneous  infection  develops  in  rats  suffering  from 
deficiency  of  vitamin  A,  there  has  been  a  bulk  of  literature  on  tliis  sub- 
ject, and  for  many  years  it  was  believed  that  vitamin  A  did  aid  in  some 
manner  in  combating  the  tendency  toward  infection  in  man.  It  is  be- 
lieved by  some  that  the  frequency  of  occurrence  and  high  fatality  rate 
of  pneumonia  in  infants,  who  suffer  from  deficiency  of  vitamin  A,  result 
from  disturbance  of  function  of  the  mucosa  of  all  parts  of  the  lung. 
Others  believe  that  the  provision  of  vitamin  A  in  large  amounts  is  bene- 
ficial in  preventing  the  common  cold,  but  this  whole  subject  is,  in  general, 
very  controversial.  Undoubtedly  severe  deficiency  of  vitamin  A  in  man 
will  lower  the  resistance  to  infection;  yet  administration  of  vitamin  A 
during  the  course  of  an  infection  apparently  does  not  have  any  beneficial 
effect  on  the  outcome  of  the  infection  unless  a  severe  deficiency  of 
vitamin  A  also  is  present.  Certainly  there  is  enough  evidence  to  indicate 
that  there  are  many  other  factors,  which  have  an  influence  on  infection 
equal  to  that  of  vitamin  A,  and  that  some  factors  have  a  greater  influence. 

Vol.  I.  948 


VITAMINS  A:  PATHOLOGICAL  PHYSIOLOGY  447 

Hence,  there  is  no  justification  for  calling  vitamin  A  "the  anti-infective 
vitamin". 

Eye.  —  Decreased  facility  for  adaptation  to  dark  is  one  of  the  earliest 
functional  changes  associated  with  deficiency  of  vitamin  A.  Evidence 
has  been  reported  which  suggests  that  the  visual  purple  of  the  retina  is  a 
conjugated  protein  in  which  vitamin  A  is  a  prosthetic  group.  Exposure 
of  the  retina  to  light  leads  to  a  chemical  change  with  bleaching  of  the 
visual  purple,  and  before  sensitivity  can  be  restored,  the  pigment  must 
be  reconstructed.  This  process  perhaps  is  reversible,  but  it  is  not  always 
efficient,  and,  therefore,  direct  supplies  of  vitamin  A  must  be  constantly 
available.  The  selection  of  color  and  other  visual  functions  depend  on 
light  of  high  intensity  associated  with  the  cones  of  the  retina,  whereas 
the  rods  are  sensitive  only  to  light  and  are  especially  adapted  to  function 
in  dim  light.  Visual  purple  is  found  only  in  the  rods  and  apparently 
serves  to  transform  the  energy  of  dim  light  into  nerve  impulses  which, 
within  limits,  vary  according  to  intensity  of  the  light.  Although  it  was 
believed  formerly  that  the  cone  played  no  part  in  the  metabolism  of 
vitamin  A,  it  has  been  demonstrated  recently  that  the  formation  of  visual 
violet  or  iodopsin  in  the  cone  takes  place  in  much  the  same  manner  as 
does  formation  of  visual  purple  in  the  rods.  In  the  experimental  animal 
as  in  man  pathological  changes  in  the  eye  occur  late.  Changes  in  both 
animals  and  man  are  essentially  the  same.  Metaplasia  of  the  epithelium 
of  the  conjunctiva  and  cornea  is  the  earliest  change  followed  by  vascu- 
larization of  the  cornea  with  edema  and  perhaps,  necrosis.  Accumulation 
of  keratin  itself  favors  infection  of  the  cornea,  which  may  lead  ultimately 
to  ulceration  and  hypopyon  keratitis. 

Liver.  —  It  has  been  well  established  that  the  liver  enacts  a  major  role 
in  the  metabolism  of  vitamin  A,  but  the  exact  manner  in  which  this  is 
accomplished  is  still  unknown.  As  early  as  1895  H^^ri  had  made  the 
clinical  observation  that  night  blindness  and  keratomalacia  frequently 
accompany  disease  of  the  liver.  Later  it  was  shown  that  in  patients,  who 
have  alcoholic  cirrhosis  without  jaundice,  there  are  subnormal  powers  of 
adaptation  to  darkness  which  improve  on  the  adequate  administration  of 
vitamin  A.  Others  have  demonstrated  repeatedly  that  the  content  of 
vitamin  A  in  the  liver  and  blood  of  patients,  who  have  severe  hepatic 
injury,  nearly  always  is  decreased  markedly. 

Low  values  for  vitamin  A  in  the  blood  have  been  reported  to  be  asso- 
ciated with  severe  hepatic  damage.  Clinical  improvement  \\as  accom- 
panied by  the  oradual  return  to  normal  of  the  content  of  vitamin  A  in 
the  blo()d'^ 

Vol..  I.  9^R 


44H  VITAMINS  AND  \  11  AiMIN  DEFICIENCY 

Human  Requirements 

Vitamin  A  is  essential  to  normal  metabolism.  Although  the  exact 
minimal  requirement  of  vitamin  A  for  man  still  is  unknown,  considerable 
work  has  been  carried  out  in  an  effort  to  settle  this  point.  Since  the 
recommended  daily  allowances  for  definite  nutrients  as  defined  by  the 
Food  and  Nutrition  Board  of  the  National  Research  Council  and  later 
adopted  by  the  Council  on  Foods  and  Nutrition  of  the  American  Med- 
ical Association  represents  the  thoughts  of  the  leaders  in  these  particular 
fields,  it  would  seem  well  that  these  should  be  accepted. 

For  the  average  man  and  woman,  who  weighs  70  and  56  kg.,  respec- 
tively, the  daily  allowance  is  5.000  international  units.  In  the  latter  half 
of  pregnancy  6,000  international  units  are  required,  and  during  lactation 
the  requirement  is  8,000  international  units.  For  children  aged  less  than 
a  year  1,500  units  are  required;  for  those  aged  one  year  to  three  years, 
2,000;  for  those  four  to  six  years  old,  2,500;  for  those  seven  to  nine  years 
old,  3,500  and  for  those  ten  to  twelve  years  old,  4,500.  For  children  more 
than  twelve  but  not  more  than  fifteen  years  of  age  5,000  units  are  re- 
quired, and  for  those  sixteen  to  twenty  years  of  age,  6,000  units.  Allow- 
ances in  all  these  instances  may  be  less,  if  the  substance  provided  is  vita- 
min A,  and  greater,  if  it  is  chiefly  the  provitamin,  carotene. 

Deficiency  of  Vitaxiin  A  in  Man 

Apparently  deficiency  of  vitamin  A  in  man  is  not  common  in  this 
country.  Normal  subjects  placed  on  a  diet  deficient  in  vitamin  A  appear 
to  have  sufficient  stores  to  maintain  vitamin  A  in  the  blood  and  tissues, 
such  as  the  retina,  at  an  adequate  level  for  many  months.  Many  investiga- 
tors have  established  that  deficiency  of  vitamin  A  is  an  uncommon  dis- 
turbance even  among  the  ill  and  poorly  nourished'**'^^.  However,  follicu- 
lar hyperkeratosis,  pityriasis  rubra  pilaris  and  cirrhosis  of  the  liver  all  arc 
diseases,  in  which  the  thresholds  of  adaptation  to  dark  have  been  found 
to  be  abnonnal,  and  in  which  these  thresholds  have  been  improved  mate- 
rially through  the  administration  of  vitamin  A. 

Epithelhivi.  —Cutaneous  lesions  (Figs.  4,  5,  6  and  7)  associated  with 
deficiency  of  vitamin  A  and  analogous  to  those  occurring  in  other  epi- 
thelial structures  have  been  reported  by  several  investigators.  The  skin 
contains,  however,  no  appreciable  vitamin  A  in  spite  of  the  fact  that  the 
vitamin  has  an  important  influence  on  cutaneous  and  structural  growth. 

Vol.  I.  948 


VITAMINS  A:  DEFICIENCY  449 

There  is  little  evidence  to  show  that  derniatological  conditions  are  influ- 
enced by,  or  influence,  the  content  of  vitamin  A  of  the  plasma"". 

In  the  skin  vitamin  A  apparently  is  concerned  with  the  process  of 
keratinization.  In  conditions  of  long-standing  deficiency  of  vitamin  A 
the  skin  becomes  dry  and  hyperkeratotic.    These  changes  are  evident 


Fig.  4.    Cutaneous   manifestations   of   vitamin    A    deficiency.     (Frazier,   C.   N.,   Hu, 
Ch'uan-K'uei  and  Chu,  Fu-T'ang:    Arch.  Dermat.  and  Syph.,   1943,  XLX^III,   i.) 

microscopically  as  follicular  hyperkeratosis,  parakeratosis  and  dyskera- 
tosis. Steffens  as  reported  by  him  and  his  associates'"^  eliminated  vitamin  A 
from  his  diet  for  a  period  of  6  months,  and  although  his  capacity  for 
adaptation  to  dark  remained  within  normal  limits,  his  skin  became  dry, 
and  there  were  microscopic  changes  in  the  skin  similar  to  those  just 
mentioned. 
Vol.  I.  948 


450  VITAMINS  AND  VITAiMIN  DEFICIENCY 

The  severe  dermatoses  of  deficiency  of  vitamin  A  are  found  in  the 
same  geographical  distribution  as  the  advanced  ocular  manifestations". 
The  lesions  consist  of  epidermal  hyperplasia  and  glandular  atrophy  and 
are  represented  by  papular  eruptions  around  the  pilosebaceous  follicles. 


Fig.  5.    Pityriasis  rubra  pilaris,  demonstrating  follicular  hyperkeratosis.    (By  cour- 
tesy of  Department  of  Dermatology,  Alayo  Clinic.) 

These  usually  occur  among  persons  betM'een  the  ages  of  16  and  30  years 
and  not  among  infants.  The  condition  is  common  among  men,  and  nearly 
all,  who  have  the  dermatosis,  also  have  obvious  ocular  manifestations  of 
deficiency  of  vitamin  A.  Reports  from  the  East  indicate  that  the  inci- 
dence of  this  symptom  is  as  high  as,  or  higher  than,  that  of  the  ocular 
symptoms"''. 
Vol.  1.  948 


VITAiMINS  A:  DEFICIENCY 


45 


Eye.  —  In  the  United  States  xerophth;ilnii:i,  kenitonialacia  and  nycta- 
lopia caused  by  deficiency  of  vitamin  A  are  rare.  The  early  pathological 
changes  are  the  same  as  those  described  previously  for  animals.  Xeroplv 
thalmia  is  most  common  in  infancy,  although  it  may  be  seen  at  all  ages. 

The  loss  of  visual  acuity  in  dim  light  is  one  of  the  first  symptoms  of 
deficiency  of  vitamin  A  in  man.  Definite  pathological  changes  in  the  eye, 
however,  occur  late  in  man  when  diets  deficient  in  vitamin  A  are  em- 
ployed-\   Night  blindness  usually  develops  in  adult  persons  before  any 


Fig.  6.    Pityriasis  rubra  pilaris,  demonstrating  keratoderma  palmaris.     (By  courtesy 
of  Department  of  Dermatology,  Mayo  Clinic.) 

types  of  ophthalmia  develop,  but  usually  the  disease  is  ushered  in  by 
small  triangular  white  patches,  which  appear  on  the  outer  and  inner  sides 
of  the  cornea,  covered  by  white,  foamlike  spots  consisting  of  corneal 
epithelium,  which  has  been  shed  and  accumulates  in  this  position,  Bitot's 
spots.  Photophobia  and  conjunctivitis  appear  early  followed  by  light 
brown  pigmentation  of  the  conjunctiva.  The  keratinization  of  the  con- 
junctiva may  extend  to  the  cornea  and  lead  to  extreme  softness  and 
degeneration  of.  the  cornea  and  to  ulceration,  perforation  and  total  de- 
struction of  the  eye,  keratomalacia.  This  disease  may  destroy  the  eye 
rapidly,  and  its  prompt  recogniti(Mi,  therefore,  is  very  important. 
Vol.  I.  948 


452  VITAMINS  AND  VITAMIN  DEFICIENCY 

For  a  number  of  years  Spies  and  associates  have  studied  the  ocular 
symptoms  occurring  as  a  result  of  mahiutrition  among  human  beings. 
Asche  and  Spies  have  observed  that  Bitot's  spots  frequently  are  observed 
among  these  patients,  and  that  they  disappear  soon  after  large  doses  of 
vitamin  A  have  been  administered.  Follicular  conjunctivitis  is  observed 
frequently,  particularly  among  children,  and  it  also  often  disappears  after 


Fig.  7.    Pityriasis  rubra  pilaris,  demonstrating  keratoderma  plantaris.    (By  courtes)- 
of  Department  of  Dermatologv,   Mayo   Clinic.) 

the  administration  of  large  amounts  of  vitamin  A.  Mild  conjunctival 
xerosis  also  has  been  attributed  to  deficiency  of  vitamin  A'"^"^"". 

Methods  for  Measuring  Deficiency  of  Vitamin  A 

The  fact  that  night  blindness  is  an  early  symptom  of  deficiency  of 
vitamin  A  led  to  the  development  of  visual  adaptation  in  dim  light  as  a 
method  for  the  diagnosis  of  deficiency  of  this  vitamin.  Whether  defi- 
ciency of  vitamin  A  can  be  measured  by  testing  adaptation  to  dark  con- 
tinues to  be  a  most  controversial  subject.  Some  contend  that  this  method 

Vol.  I.  948 


VITAMINS  A:  A/IETHODS  OF  MEASURING  452(1) 

is  satisfactory  for  measuring  deficiency  of  vitamin  A.  Others  contend 
that,  although  some  relationship  exists  between  readiniTs  of  the  biopho- 
tometer  and  the  status  of  nutrition  of  vitamin  A,  yet  the  relationship  is 
not  close  enough  to  warrant  use  of  the  test  as  a  means  of  diagnosis  of 
subclinical  deficiency  of  vitamin  A.  It  has  been  pointed  out  that  the 
method  is  time-consuming,  and  that  for  this  reason  alone  its  routine  clini- 
cal use  practically  is  ruled  out.  Certainly  minor  fluctuations  in  adaptation 
to  dark  in  terms  of  deficiency  of  vitamin  A  should  receive  little  emphasis 
unless  physical  methods  are  used  to  test  the  reliability  of  the  differences. 
It  is  true  that  a  majority  of  workers  believe  that  the  study  of  adaptation 
to  dark  can  be  used  as  a  test  for  deficiency  of  vitamin  A,  but  until  differ- 
ences in  technic  and  in  interpretation  of  results  have  been  resolved,  it  is 
impossible  to  be  certain  how  far  recorded  observations  represent  physio- 
logical facts.  In  fact,  by  having  human  beings  subsist  on  a  diet  deficient 
in  vitamin  A  over  long  periods  some  investigators  have  been  unable  to 
produce  clinical  night  blindness  or  even  changes  in  adaptation  to  dark"^ 
It  may  be,  as  stated  by  Josephs"^  that  all  this  discrepancy  is  the  result  of 
lack  of  knowledge  of  methods  for  determining  storage  of  vitamin  A. 
Certainly  at  present  there  is  no  single  simple  formula  for  computing  the 
needs  of  the  body  for  vitamin  A.  Measurements  of  dark  adaptation  pro- 
vide only  one  approach  to  the  subject. 

No  definite  correlation  between  biophotometer  readings  and  the  con- 
tent of  vitamin  A  in  the  blood  has  been  observed.  Although  it  has  been 
demonstrated  that  the  amount  of  vitamin  A  in  the  blood  is  dependent  on 
the  amount  provided  in  the  diet,  yet  evidence  as  to  whether  determina- 
tion of  vitamin  A  in  the  blood  is  of  value  in  judging  the  nutriti<jnal  status 
still  is  contradictory.  Recently  evidence  has  been  presented,  which  sug- 
gests that  the  concentration  of  vitamin  A  in  the  blood  plasma  is  a  consid- 
erably more  sensitive  indicator  of  deficiency  of  vitamin  A  than  is  the 
test  for  adaptation  to  dark. 

The  same  contradictory  evidence  is  presented  for  the  measurement 
of  vitamin  A  by  examination  of  scrapings  from  the  eye  and  vagina.  On 
the  basis  of  results  of  all  of  these  studies  it  would  be  judged  that  the 
methods  for  measuring  deficiency  of  vitamin  A  of  man  still  are  somewhat 
unreliable  and  demand  further  study.  Among  some  physicists  and  chem- 
ists there  still  is  doubt  as  to  whether  the  small  quantities  of  vitamin  A 
present  in  the  blood  stream  of  man  can  be  measured  with  the  chemical 
methods  available. 

\^oi..  I.  948 


452(2)  VITAMINS  AND  VITAiUIN  DEFICIENCY 

Toxicity 

If  large  amounts  of  vegetables  containing  carotene  are  ingested  by 
nomial  persons  and  persons  suffering  from  certain  diseases  such  as  dia- 
betes, carotene  may  accumulate  in  the  skin  in  amounts  sufficient  to  cause 
a  deep  yellow  color.  Such  a  condition  is  known  as  carotenemia.  This 
condition,  so  far  as  is  known,  is  compatible  with  good  health. 

It  is  difficult  to  evaluate  the  reports  concerning  the  injurious  effects 
on  man  which  follow  the  ingestion  of  cod  liver  oil.  Some  obsen^ers, 
when  administering  large  doses,  80  c.c,  of  cod  liver  oil,  have  noticed  the 
appearance  of  dermatitis  of  the  face  and  scalp.  Sensitivity  to  cod  liver  oil 
resulting  in  eczema  also  has  been  reported.  However,  on  the  basis  of  the 
general  favorable  clinical  results  of  the  use  of  cod  liver  oil  and  other 
preparations  containing  vitamin  A  the  physician  should  be  extremely 
certain  that  it  is  harmful  before  he  discontinues  its  use.  Certainly,  when 
the  averaq'e  therapeutic  dose  is  employed,  no  such  toxic  effect  will  be 
observed. 

It  has  been  reported  recently  that  in  growing  rats,  given  the  purest 
available  fomi  of  vitamin  A  in  excess,  skeletal  fractures  and  hemorrhage 
develop  rather  characteristically'"'. 

Diagnosis  of  Vitamin  A  Deficiency 

Undoubtedly  the  incidence  of  marked  deficiency  of  vitamin  A  in 
the  United  States  is  very  small.  Of  course  the  supposition  that  states  of 
partial  deficiency  may  be  common  has  received  repeated  emphasis,  but 
as  yet  no  definite  methods  have  been  developed  by  which  these  subnutri- 
tional  states  can  be  diagnosed. 

Night  Blindness.  —  The  first  symptom  of  this  syndrome  is  loss  of 
visual  acuity  in  dim  light.  This  particular  symptom  may  occur  in  the 
presence  of  various  diseases  of  the  eve  such  as  toxic  amblyopia,  detach- 
ment of  the  retina  or  retinitis  pigmentosa,  but  these  conditions  usually 
are  excluded  easily.  The  patient  may  complain  of  dancing  lights  before 
his  eyes  or  similar  visual  disturbances,  and  of  course,  by  means  of  testing 
for  adaptation  to  dark  he  will  exhibit  a  pathological  condition.  This  con- 
dition must  be  suspected  in  cirrhosis  of  the  liver,  instances  of  severe  and 
prolonged  pyloric  obstruction,  severe  chronic  diarrhea  and  any  other 
condition  which  may  produce  a  generalized  nutritional  deficiency. 

Xerophtbahnia.  —  The  symptoms  of  xerophthalmia  have  been  given 
already  under  the  heading,  "Deficiency  of  Vitamin  A  in  Man— £}'e". 

Vol.  I.  948 


VITAMINS  A:  TREATMENT  452(3) 

Lesions  of  the  Skin.  —  Within  the  past  few  years  several  groups  of 
investigators  have  reported  on  patients  who  had  cutaneous  lesions  which 
were  considered  to  be  the  result  of  a  deficiency  of  vitamin  A.  These 
lesions  are  shown  best  in  Figs.  4,  5,  6  and  7.  Many  investigators  believe 
that  this  manifestation  of  deficiency  of  vitamin  A  is  overlooked  fre- 
quently. 

SiihcVmicitl  Form.— It  is  practically  impossible  to  cHnically  diagnose 
subcHnical  deficiency  of  vitamin  A.  These  forms  probably  are  frequent, 
however,  and  must  be  considered  under  various  conditions  in  which 
inability  to  carrv  out  proper  absorption  or  proper  intake  or  utilization  of 
vitamin  A  is  suspected. 

Differential  Diagnosis 

Although  various  laboratory  procedures,  such  as  measurement  of  the 
content  of  vitamin  A  in  the  blood  and  testing  for  adaptation  to  dark,  in 
time  may  be  very  helpful  in  diagnosis  of  deficiency  of  vitamin  A,  the 
best  method  of  differential  diagnosis  still  depends  on  close  clinical  ob- 
servation. Nig;-ht  blindness,  xerophthalmia  and  keratomalacia  are  not  con- 
fused easily  with  any  other  conditions  and  should  be  recognized  readily. 
Treatment  should  be  instituted  at  once. 


Treatment  of  A^itaaiix  A  Deficiency 

The  use  of  vitamin  A  in  treatment  is  indicated  in.  those  syndromes, 
which  result  from  deficiency  of  vitamin  A  in  the  diet  or  from  deficiency 
of  vitamin  A  resulting  from  improper  absorption  or  utilization.  The  best 
treatment  with  vitamin  A  still  involves  prophylactic  therapy.  In  general 
the  response  to  treatment  with  vitamin  A  of  specific  syndromes  resulting 
from  the  deficiency  is  slow,  and  recovery  may  involve  weeks  and  months 
of  time. 

Persons,  who  possess  normal  powers  of  absorption  of  carotene  and 
vitamin  A  and  who  have  night  blindness,  may  be  treated  by  diet  alone  or 
diet  plus  vitamin  A  supplement.  In  those  cases,  in  which  night  blindness 
results  from  faulty  absorption  such  as  is  caused  by  gastrocolic  fistula, 
gastrointestinal  continuity  first  must  be  re-established  before  treatment, 
unless  the  compounds  are  administered  intramuscularly. 

Xerophthalmia  and  keratomalacia  require  the  same  treatment  as  night 
blindness,  but  it  is  perhaps  wise  to  administer  doses  of  from  50,000  to 

Vol.  I.  948 


452(4)  VITAA4INS  AND  VITAMIN  DEFICIENCY 

100,000  units  in  the  form  of  potent  fish  liver  oil  by  the  oral  or  parenteral 
route. 

In  the  presence  of  lesions  of  the  skin  the  best  results  have  been  ob- 
tained from  doses  of  100,000  to  300,000  international  units  of  vitamin  A 
administered  daily  over  a  period  of  two  to  three  months.  It  must  be  re- 
membered that  results  of  treatment  of  lesions  of  the  skin  require  periods 
of  2  to  3  months,  and  the  physician  should  not  become  discouraged 
because  there  is  not  a  dramatic  response. 

^^^^en  patients  who  have  chronic  diarrhea  are  being  treated,  it  should 
be  borne  in  mind  that  these  patients  require  more  vitamin  A  than  is  nec- 
essary for  normal  persons.  Patients,  who  have  hepatic  disease,  likewise 
require  rather  large  doses  of  the  vitamin.  In  such  instances  from  10,000 
to  20,000  international  units  of  vitamin  A  administered  daily  is  consid- 
ered to  be  an  adequate  dose.  A  person,  from  whose  intestinal  tract  bile  is 
excluded  completely  or  partially,  should  be  given  supplements  of  bile 
salts  with  vitamin  A  supplement. 

Obviously  in  the  treatment  of  any  of  these  conditions  diets  rich  in 
vitamin  A  and  its  precursors  should  be  prescribed  in  addition  to  the 
potent  supplement  containing  vitamin  A. 


\ Oi..  1.  948 


VITAMINS  D 


452(5) 


VITAiVIINS  D 

There  is  little  doubt  that  rickets  has  been  prevalent  for  many  cen- 
turies. It  was  not,  however,  until  about  1882  that  cod  liver  oil  was  sug- 
gested as  a  remedy  for  the  condition"'.  Hopkins'"  susraested  that  rickets 
was  caused  by  the  absence  of  an  accessory  foodstuff,  and  in  191 3  the 
beneficial  influence  of  sunlight  on  the  assimilation  of  calcium  was  re- 
ported. 

It  was  A4ellanby^\  however,  who  in  19 18  discovered  the  nutritional 
importance  of  animal  fats  in  the  normal  calcification  of  bones,  and  who 
concluded  that  the  antirachitic  factor  was  similar  in  distribution  to  fat- 
soluble  A.  Later  rickets  was  induced  in  rats  by  special  diet,  and  Steen- 
bock  and  Black^-  as  well  as  Hess^^  found  that  antirachitic  potency  could 
be  induced  in  foods  by  ultraviolet  irradiation.  McCollum  named  the  anti- 
rachitic material  "vitamin  D". 


MeCH  CH:CH  CHCH^ 
Me 


eCHCHj-CHj-CHi-CH^ 


,M« 


CcJcifepol    (Vitamin   Da)  Activated    T-dghydro-cholesterol    (Vitamin  Dj) 

F'g-S  Fig.  9 

Fig.  8.    The  structural  formula  for  calciferol    (vitamin   D2). 
Fig.  9.    The  structural  formula  for  activated  7-dehydrocholesterol   (vitamin  D3). 

ChExMISTRY 

A  compound,  which  can  be  activated  to  a  vitamin  D,  is  known  as  a 
"provitamin  D".  These  compounds  belong  to  the  sterol  family  and  are 
distributed  widely  over  the  animal  and  plant  kingdoms.  The  most  preva- 
lent provitamin  D  in  higher  animals  and  in  human  beings  is  y-dehydro- 
cholesterol,  whereas  ergosterol  is  predominant  in  yeast,  molds  and  plants. 
Activated  ergosterol,  viostcrol  or  calciferol  is  known  as  "vitamin  D2" 
(Fig.  8)  and  activated  y-dehydrocholesterol  is  known  as  "vitamin  D3" 
(Fig.  9).  There  is  no  vitamin  Di,  this  term  having  been  used  for  a 
lumisterol-calciferol  mixture  originally  mistaken  for  a  pure  vitamin. 
"Vitamin  D4"  is  the  term  sometimes  applied  to  activated  22-dihydro- 
ergosterol,  and  "vitamin  Dr."  sometimes  is  referred  to  as  y-dehydro- 
sitosterol. 

Vol..  I.  948 


452(6)  VITAAIINS  AND  \  1  lAAIIN  DliFICIEXCV 

E>gosteroI  has  the  empirical  formula,  C2SH44O.  The  conversion  of 
this  provitamin  to  vitamin  D  is  not  a  simple  process  but  involves  a  series 
of  photochemical  changes  which  are  initiated  when  ergosterol  is  exposed 
to  ultraviolet  light.  During  this  reaction  several  substances  are  formed, 
lumisterol,  pro-tachvsterol,  tachysterol  and  finally,  calciferol  (vitamin 
Di>).  Further  irradiation  of  vitamin  D2  produces  a  toxic  compound, 
which  has  no  antirachitic  activity  and  is  kno^^'n  as  "toxisterol". 

Inactive  7-dehydrocholesterol  is  the  principal  provitamin  occurring 
with  the  cholesterol  of  animal  fat.  Ultraviolet  irradiation  of  the  skin, 
feathers  and  fur  of  animals,  therefore,  produces  activated  y-dehydro- 
cholesterol.  For  this  reason  the  principal  antirachitic  agent  present  in 
natural  fat  oils,  eggs  and  irradiated  milk  is  activated  7-dehydrochol- 
esterol. Just  as  in  the  case  of  ergosterol  the  changes  produced  by  the 
activation  of  7-dehydrocholesterol  are  entirely  photochemical.  The 
physical  and  chemical  properties  of  y-dehydrocholesterol  resemble  those 
of  calciferol.  Both  of  these  substances  have  been  isolated  in  crystalline 
form,  but  attempts  at  synthesis  have  been  unsuccessful. 

Dihydro-tachy sterol  is  a  sterol  of  considerable  practical  importance. 
It  is  prepared  from  the  acid  ester  of  tachysterol  and,  when  administered 
to  human  beings,  causes  an  increase  of  the  concentration  of  calcium  in 
the  blood.  In  therapeutic  circles  it  is  known  as  "A.T.io",  and  it  is  useful 
in  infantile  and  postoperative  hypoparathyroid  tetany. 

The  isolation  and  identification  of  the  pure  vitamins  D  have  been 
most  difficult  tasks.  The  exact  number  of  naturally  occurring  vitamins  D 
is  unknown,  but  only  four  vitamins  designated  "D2,  Ds,  D4"  and  "D.-;" 
have  been  prepared  in  essentially  pure  fomi.  Only  vitamin  D2  and  vita- 
min D3  have  been  isolated  in  the  pure  form  from  fish  liver  oils.  These 
vitamins  are  fat  soluble,  and  in  the  pure  state  are  white,  odorless  crystals. 
V'itamin  D2  (Fig.  8)  is  an  isomer  of  ergosterol,  from  which  it  is  derived, 
and  it  has  the  empirical  formula,  C2SH44O.  Vitamin  D3  (Fig.  9)  can  be 
derived  from  7-dehydrocholesterol. 


Physiology 

Absorption  and  Storage.  — The  various  forms  of  vitamin  D  are  ab- 
sorbed readily  from  the  intestinal  tract  and  especially  from  the  small 
bowel.  This  absorption  is  facilitated  by  the  presence  of  fat,  but  bile  salts 
also  are  necessary  for  proper  absorption.  Recent  investigations  indicate 
that  the  salts  of  desoxycholic  acid  may  be  concerned  particularly  with 

Vol.  I.  948 


VITAMINS  D:   PHYSIOLOGY  452(7) 

the  absorption  of  the  liposoluble  vitamins.  The  factor  of  absorption  also 
enters  into  such  diseases  as  cehac  disease,  sprue  and  other  fatty  diarrheas 
which  are  attended  commonly  by  deficiency  of  vitamin  D. 

From  the  intestines  vitamin  D  is  said  to  be  absorbed  into  the  blood. 
There  is  also  some  evidence  to  show  that  most  of  the  vitamin  D  is  ab- 
sorbed first  into  the  lymph  of  the  thoracic  duct,  and  that  its  rate  of 
absorption  is  comparable  to  that  of  vitamin  A^^  Nomial  human  blood 
contains  about  50  to  135  international  units  per  100  c.c.  of  serum.  The 
human  being  apparently  has  no  special  place  for  storage  of  vitamin  D, 
although  substantial  amounts  can  be  found  in  organs  such  as  the  liver, 
spleen,  brain  and  lungs.  The  heart  has  been  found  consistently  to  be 
devoid  of  any  stored  amounts  of  vitamin  D.  Failure  of  this  storage  mech- 
anism, coupled  M'ith  defective  secretion  of  bile  salts,  may  lead  to  sec- 
ondary avitaminosis  D  in  cases  of  hepatobiliary  disease.  This  possibility 
has  been  emphasized  further  by  the  observation  that  in  animals  normal 
hepatic  function  is  necessary  to  promote  the  antirachitic  action  of 
vitamins. 

Apparently  vitamin  D  can  pass  only  in  limited  amounts  through  the 
placental  walls.  Newborn  babies  have  practically  no  vitamin  D  in  their 
tissues,  even  though  their  mothers  had  an  abundant  supply  during  gesta- 
tion. Recent  data  clearly  indicate  that  the  ability  to  increase  the  vitamin 
D  content  of  human  milk  or  co\a''s  milk  by  large  oral  doses  of  vitamin  D 
is  very  limited.  Even  when  massive  doses  were  ingested  daily  by  a 
mother,  the  antirachitic  potency  of  the  milk  was  insufficient  completely 
to  prevent  rickets  in  the  breast-fed  infant^^ 

No  results  of  quantitative  studies  are  available  which  would  indicate 
how  much  destruction  of  vitamin  D  occurs  in  the  organism.  Obviously 
some  is  destroyed,  and  some  is  excreted  mainly  through  the  bile  and 
intestinal  tract  but  not  through  the  kidneys. 

The  concentration  of  vitamin  I)  in  the  blood  of  human  beings  has 
been  studied  inadequately.  Observations  indicate  that  there  is  a  wide 
zone  of  so-called  normal  concentration  varying  from  66  to  165  U.S.P. 
units  per  100  c.c.  of  blood. 

Ccilchivi  and  Phosphorus  Metabolisiu.  —  Vitamin  D  is  concerned 
chiefly  with  the  regulation  of  calcium  and  phosphorus  in  the  bod\-,  but 
the  exact  chemical  nature  of  this  mechanism  is  not  understood  clearly. 
No  one  yet  has  demonstrated  whether  vitamin  D  enters  directly  into  the 
combination  with  these  elements  or  their  salts  or  merely  assumes  the  role 
of  catalyst.  However,  it  can  be  demonstrated  easily  that  the  growth  of 
bones  is  related  to  the  action  of  vitamin  D.  An  early  symptom  of  defi- 

VOL.  I.  948 


452(8)  MTA.MTNS  AND  VITAMIN  DEFICIENCY 

ciency  of  vitamin  D  is  a  lowered  content  of  phosphorus  in  the  blood 
serum  and  later,  a  lowering  of  the  blood  level  of  calcium. 

In  general  the  concentrations  of  calcium  and  phosphorus  in  the  blood 
serum  reflect  the  amounts  of  these  elements  ingested.  The  ratio  of  these 
elements  seems  to  be  important  in  the  rachitogenic  diet,  since  a  high- 
calcium  and  low-phosphorus  diet  is  associated  with  a  low  content  of 
inorcranic  phosphate  in  the  blood  serum  and  vice  versa.  The  absolute 
amount  as  well  as  the  ratio  determines  the  content  of  calcium  and  phos- 
phorus in  the  body  fluids,  and  these  values  increase  as  the  amounts  given 
are  increased.  However,  in  the  presence  of  an  adequate  amount  of  vita- 
min D  the  values  for  calcium  and  phosphorus  in  the  serum  tend  to 
become  normal  regardless  of  the  type  of  diet  employed. 

Although  secondary  in  importance  to  the  calcium-phosphorus  ratio 
the  acid-base  ratio  of  the  diet  may  be  a  factor  in  the  production  of  rickets 
or  tetany.  There  is  some  evidence  to  show  that  rickets  is  associated  with 
an  acid  metabolism  and  tetany  with  an  alkaline  one.  In  neither  of  these 
conditions,  whether  it  occurs  clinically  or  is  produced  experimentally  in 
animals,  is  there  a  definite  alteration  of  the  acid-base  equilibrium  of  the 
blood. 

The  action  of  vitamin  D  on  calcium  and  phosphorus  metabolism 
seems  to  be  concerned  chiefly  with  the  absorption  of  the  elements  from 
the  intestinal  tract.  The  nomial  infant  excretes  about  90  per  cent,  of  his 
calcium  intake  in  the  feces  and  usually  excretes  a  small  amount  in  the 
urine.  When  vitamin  D  is  not  given,  the  calcium  in  the  urine  disappears. 
This  is  an  attempt  on  the  part  of  the  body  at  conservation  of  minerals. 
The  concentration  of  calcium  in  the  feces  increases,  and  the  retention  of 
calcium  becomes  subnormal.  If  the  intake  of  calcium  is  low  or  the  defi- 
ciency severe,  the  fecal  calcium  actually  may  exceed  the  intake,  and  thus 
the  condition  known  as  "negative  calcium  balance"  ensues.  A  similar 
sequence  of  events  occurs  in  the  case  of  phosphorus,  except  that  the 
amount  of  phosphate  contained  in  the  urine  usually  is  increased^"'^". 

The  effect  of  vitamin  D  in  producing  a  reversal  of  these  conditions 
is  striking.  The  intestinal  excretion  of  calcium  and  phosphorus  is  de- 
creased, calcium  appears  in  the  urine,  and  the  calcium  balance  is  restored 
to  normal.  The  changes  in  the  concentration  of  calcium  and  phosphorus 
in  the  serum  are  reflectors  of  this  calcium  balance. 

In  recent  years  it  has  been  sho\\'n  that  there  exists  in  the  body  an 
en/yme,  phosphatase,  which  is  intimately  related  to  phosphorus  metab- 
olism. The  exact  function  of  phosphatase  in  the  serum  is  not  known,  but 
whatever  it  may  be,  there  is  no  question  that  in  diseases  of  the  bone,  and 
Vol.  I.  948 


VITAMINS  D:  FOOD  SOURCES  452(9) 

especially  resorptive  ones  in  which  osteoblastic  activity  is  increased,  the 
concentration  of  phosphatase  in  the  serum  is  increased.  Such  is  the  case 
in  rickets.  An  increase  in  the  concentration  of  phosphatase  in  the  serum 
is  perhaps  the  first  definite  evidence  of  development  of  the  rachitic  con- 
dition; it  precedes  roentgenological  changes  and  diminution  of  the 
amount  of  serum  phosphate.  The  concentration  of  serum  phosphatase  is 
high  in  cases  of  active  rickets,  and  the  administration  of  vitamin  D  de- 
creases the  concentration  toward  normal  but  more  slowly  than  it  de- 
creases the  concentration  of  calcium  and  phosphorus.  The  concentration 
of  phosphatase  may  not  reach  normal  for  several  months  after  there  is 
evidence  of  healing.  The  increase  of  the  concentration  of  serum  phos- 
phatase in  cases  of  rickets  apparently  acts  as  a  protective  mechanism. 

The  difference  in  action  between  vitamin  D  and  parathyroid  extract 
is  often  the  source  of  confusion,  and  it  is  important  to  the  clinician  that 
this  distinction  be  clear.  Although  both  preparations  increase  the  concen- 
trations of  calcium  and  phosphorus  in  the  serum,  parathyroid  extract 
acts  specifically  on  the  serum  calcium,  and  in  parathyroid  tetany  it  may 
even  decrease  the  concentration  of  serum  phosphate.  In  cases  of  rickets 
the  principal  action  of  vitamin  D  is  in  raising  the  low  concentration  of 
serum  phosphate;  only  when  administered  in  very  large  doses  does  it 
raise  the  concentration  of  serum  calcium  to  more  than  normal.  Parathy- 
roid extract  increases  the  concentration  of  serum  calcium  by  withdraw- 
ing the  element  from  the  bone;  vitamin  D  exerts  this  effect  by  increasing 
the  intestinal  absorption  of  calcium  or  by  diminishing  its  re-excretion 
from  the  intestinal  mucosa.  The  distinction  may  be  clearer,  if  the  reader 
remembers  that  the  toxic  effect  of  parathyroid  extract  is  decalcification 
but  that  that  of  vitamin  D  is  hypercalcification. 

Although  the  parathyroid  glands  have  been  shown  to  undergo  hyper- 
trophy in  cases  of  rickets,  this  is  a  result,  rather  than  the  cause,  of  rickets. 
Indeed,  injections  of  parathyroid  extract  have  been  shown  to  retard  the 
healing  of  rickets,  and  removal  of  the  parathyroid  glands  from  animals 
makes  the  production  of  rickets  more  difficult. 

Fooo  Sources 

Vitamin  D  occurs  in  nature  only  in  small  amounts.  Only  in  small 
quantities,  likewise,  does  it  occur  in  most  members  of  the  animal  king- 
dom. The  living  plant  and  fresh  vegetables  contain  no  detectable  amount 
of  this  vitamin. 

Although  the  fat  from  fish  contains  relatively  lars^e  amounts  of  vita- 

Voi..  T.  948 


452 (lo)  VITAMINS  AND  VITAMIN  DEFICIENCY 

min  D,  the  fat  of  other  animals  contains  little  or  none  of  it.  A  very  small 
amount  of  the  vitamin  is  present  in  milk  and  milk  products  and  in  the 
yolk  of  hen's  eggs.  Sardines,  tuna,  herring  and  salmon,  either  fresh  or 
canned,  are  fairly  good  sources  of  the  vitamin.  The  average  diet,  how- 
ever, contains  relatively  small  amounts  of  vitamin  D. 

The  accepted  standard  unit  for  expressing  the  strength  of  vitamin 
D  as  adopted  by  the  League  of  Nations  Health  Organisation  and  by  the 
United  States  Pharmacopoeia  is  defined  as  "The  vitamin  D  activity  of 
I  mgm.  of  the  international  standard  solution  of  irradiated  ergosterol 
found  equal  to  0.025  niicrograms  of  crystalline  vitamin  D".  This  is  the 
international  unit  (I.U.)  accepted  as  the  U.S.P.  unit.  In  administering 
antirachitic  agents  the  physician  should  think  in  terms  of  units  of  vitamin 
D,  since  this  is  the  only  way  in  which  the  doses  of  the  various  substances 
containino-  vitamin  D,  which  differ  greatly  in  volume,  can  be  reduced  to 
a  common  denominator.  For  example,  i  teaspoonful,  4  c.c,  of  cod  liver 
oil  contains  approximately  350  units,  i  quart  of  reinforced  milk,  400 
units  and  i  mgm.  of  calciferol,  400,000  units. 

The  most  satisfactory  sources  of  vitamin  D  are  fish  liver  oils.  The 
vitamin  D  in  cod  liver  oil  probablv  is  chiefly  activated  7-dehydrocholes- 
terol.  Cod  liver  oil  is  universally  obtainable  and  is  effective  in  the  pre- 
vention and  treatment  of  any  deficiency  of  vitamin  D.  There  is  great 
variation  in  the  concentration  of  vitamins  A  and  D  in  the  oils  obtained 
from  different  species  of  fish.  The  oil  of  the  Fercoiiiorpbi  exhibits  the 
greatest  concentration  of  vitamin  D.  Fish  oils  are  prepared  by  the  manu- 
facturer by  combining  oils  from  various  species  in  such  a  way  that  the 
final  mixture  has  a  concentration  of  vitamin  D  equal  to  that  of  viosterol 
in  oil.  These  preparations  have  the  merit  of  providing  vitamins  D  and  A 
in  high  concentrations,  so  that  both  can  be  administered  in  doses  meas- 
ured in  drops.  The  disadvantage  of  unpleasant  taste  is  again  encountered, 
but  the  quantity  required  is  small,  so  that  the  disagreeable  taste  is  not  a 
serious  disadvantage.  Vitamin  D  in  these  preparations  has  chiefly  the 
form  of  activated  7-dehvdrocholesterol. 

According  to  the  United  States  Pharmacopoeia,  cod  liver  oil  must 
contain  at  least  100  units  of  vitamin  D  per  gram.  When  large  dosage  of 
vitamin  D  is  required,  more  concentrated  sources  of  vitamin  D  usually 
are  employed.  One  gram  of  viosterol  in  oil  contains  "at  least  10,000  units 
of  vitamin  A"  to  meet  the  requirements  of  the  United  States  Pharma- 
copoeia, twelfth  revision.  The  special  dropper  accompanying  commer- 
cial preparations  is  designed  to  deliver  a  drop  containing  222  units.  The 

Vol.  I.  948 


VITAMINS  D:  PATHOLOGICAL  PHYSIOLOGY     452(11) 

vitamin  D  content  of  viosterol  is  100  times  that  of  standard  cod  liver  oil. 
Viosterol  owes  its  vitamin  D  activity  to  activated  ergosterol. 

Viosterol  in  oil  is  tasteless,  which  obviates  the  difficulty  of  adminis- 
tration encountered  in  the  case  of  cod  liver  oil.  Viosterol  suffers  one 
disadvantage  as  compared  w^ith  cod  liver  oil  and  other  fish  oils,  that  is, 
it  does  not  contain  vitamin  A.  However,  its  tastelessness  makes  it  one  of 
the  best  vehicles  for  administering  vitamin  D  to  adults  and  older  children. 

Irradiated  vitamin  D  milk  is  also  a  source  of  vitamin  D.  A^itamin  D 
activity  is  added  to  milk  of  this  type  by  exposure  to  active  ultraviolet 
rays  from  artificial  sources.  The  irradiation  is  accomplished  in  such  a 
manner  that  standardization  is  fixed  at  135  international  units  per  quart. 
It  has  been  found  impracticable  to  irradiate  the  milk  further  because  of 
the  production  of  an  unpleasant  taste.  In  irradiated  milk  the  vitamin 
occurs  chiefly  in  the  form  of  activated  7-dehydrocholesterol. 

The  various  sources  of  vitamin  D  vary  in  potency  but  may  be  sub- 
stituted for  each  other  on  the  basis  of  unitage.  Much  work  has  been  done 
to  determine  whether  there  is  any  difference  in  the  antirachitic  activity 
of  the  various  chemical  forms  of  vitamin  D.  The  only  conclusion  that 
has  been  reached  at  present  is  that  there  is  no  essential  difference. 

In  spite  of  the  numerous  claims  for  various  preparations  of  vitamin  D 
in  oil,  cod  liver  oil  is  still  the  most  economical  form  in  which  to  obtain 
the  vitamin.  Cod  liver  oil  or  one  of  the  concentrated  fish  oils  seems 
preferable  to  the  preparations  containing  viosterol,  if  for  no  other  reason 
than  that  it  seems  advisable  to  prescribe  a  preparation  of  vitamin  D, 
which  is  also  rich  in  vitamin  A.  rather  than  one  which  contains  only 
vitamin  D. 

ExPERIMENTAr  PaTHOT^OGICAL  PhYSTOLOGY 

According  to  ^^'olbach  and  Bessey^^  experimental  rickets  in  animals 
duplicates  completely  the  spontaneous  disease  in  man  and  in  animals.  To 
understand  better  the  changes  in  bone,  which  occur  in  a  deficiency  of 
vitamin  D,  the  normal  sequence  in  the  growth  of  bones  must  be  under- 
stood. Long  bones  increase  in  length  by  the  endochondral  formation  of 
bone.  The  narrow  place  of  epiphyseal  cartilage  is  supported  by  bone  on 
the  epiphyseal  surface,  and  its  diaphyseal  side  is  penetrated  uniformly  by 
capillaries.  During  growth  continuous  proliferation  of  cartilage  cells 
occurs  on  the  epiphyseal  side,  and  there  is  degeneration  of  matured  cells 
on  the  diaphyseal  surface.  These  degenerating  cells  are  replaced  by  cap- 
illaries and  osteoblasts,  which  affect  the  deposition  of  bony  matrix. 

Vol.  I.  948 


452(12)  VITAMINS  AND  VITAA/IIN  DEFICIENCY 

Wolbach  said  that  the  growth  of  bone  by  endochondral  formation  of 
bone  is  achieved  "by  a  continuously  retreating  gap  in  the  continuity  of 
tissues  maintained  on  the  epiphyseal  side  by  continuous  renewal  of  carti- 
lage cells  and  on  the  diaphyseal  side  repaired  by  vascular  outgrowth 
comparable  to  repair  of  any  defect  of  tissues  by  the  process  of  organiza- 
tion or  granulation  tissue  formation.  In  normal  growth  there  presents  on 
the  diaphyseal  side  of  the  narrow  cartilage  a  continuous  layer  of  clear 
or  empty  cartilage  cells  forming  an  almost  straight  line." 

The  cessation  of  the  fomiation  of  osteoblasts  is  the  first  sign  of  defi- 
ciency of  vitamin  D  in  the  bone.  The  growth  of  the  cartilage,  however, 
continues.  The  epiphyseal  cartilage  increases  in  width  because  of  con- 
tinued proliferative  activity,  and  this  thickening  is  irregular,  since  the 
cessation  of  degeneration  does  not  occur  simultaneously  in  all  portions 
of  the  plate.  In  the  absence  of  the  ingrowth  of  capillaries  and  osteoblasts 
there  is  a  failure  of  calcification  of  the  cartilaginous  matrix,  and  newly 
formed  bones  during  the  active  stage  of  the  disease  have  an  osteoid  struc- 
ture. The  basic  structural  alteration  in  rickets  is  not  the  failure  of  forma- 
tion of  bone  but  the  failure  of  calcification. 

The  disturbance  manifests  itself  most  markedly  where  the  most 
rapid  growth  occurs,  for  example,  at  the  lower  epiphysis  of  the  femur. 
Longitudinal  sections  of  a  rachitic  bone  will  reveal  a  wide,  irregular  zone 
of  ossification  at  the  junction  of  the  epiphysis  and  diaphysis.  This  region 
is  knoNMi  as  the  "rachitic  zone".  Microscopically  a  large  amount  of 
osteoid  tissue  is  found  adjacent  to  the  shaft,  and  irregular  columns  of 
cartilage  cells  project  into  this  osteoid  tissue.  Growth  of  the  bone  is 
delayed  or  stopped  completely  in  proportion  to  the  severity  of  the 
process.  On  microscopic  examination  of  sections  of  the  shaft  osteoid 
lamellae  are  found  under  the  periosteum  and  lining  the  haversian  canals 
and  marrow  spaces.  The  structural  changes  in  the  bone  are  not  identical 
in  every  case.  In  one  type  of  the  disease  there  is  a  large  medullary  cavity 
with  a  thin,  porous  cortex,  a  form  approaching  osteomalacia.  In  another 
type  the  cortex  is  thick  but  porous,  and  the  medullary  cavity  is  small. 

The  bony  deformities  resulting  from  these  alterations  vary  according 
to  the  amount  of  stress  to  which  the  individual  bones  are  subjected. 
Before  the  infant  walks  there  may  be  flattening  of  the  occiput  resulting 
from  the  weight  of  the  head,  since  the  excess  of  osteoid  tissue  in  the 
occipitoparietal  bones  makes  them  soft  and  yielding,  craniotabes.  There 
is  enlargement  of  the  costochondral  junctions,  rickety  rosary,  and  altera- 
tions in  the  bony  thorax  may  give  rise  to  various  deformities,  Harrison's 
groove,  pigeon  breast,  funnel  breast.  The  weight  of  the  body  produces 

Vol.  I.  948 


VITAMINS  D :  HUMAN  REQUIREiMENT  452(13) 

deformities  of  the  lower  extremities  from  the  bending  of  the  bones  in 
children  who  have  assumed  the  erect  posture  (Fig.  10).  Growth  of  the 
long  bones,  particularly  the  femur,  may  be  greatly  delayed,  and  the  adult 
may  be  of  short  stature  as  a  result.  The  epiphyses  are  enlarged,  and  it  is 
not  uncommon  for  genu  valgum  or  genu  varum  to  develop.  Occasional 
instances  of  dwarfism  have  a  rachitic  basis.  Deformities  of  the  spinal 
column  are  not  common. 

In  late  rickets  the  changes  are  similar  to  those  of  early  rickets  except 
that  the  osteoid  tissue  develops  in  the  subperiosteal  and  endosteal  por- 
tions rather  than  at  the  epiphysis.  Osteomalacia  presents  a  similar  picture. 

The  effect  of  vitamin  D  in  reversing  these  changes  has  been  demon- 
strated clearly  with  experimental  animals.  After  it  has  been  administered, 
the  cartilage  cells  generally  appear  along  the  diaphyseal  border  at  the 
end  of  24  hours,  and  extensive  vascular  penetration  is  visible  within  48 
hours;  this  permits  the  deposition  of  bone-forming  salts.  The  mass  of 
irregular  cartilage  cells  becomes  arranged  into  short,  orderly  columns  of 
a  few  cells,  and  osteoid  material  is  no  longer  formed.  This  is  the  basis  of 
the  line  test  as  used  in  assay  of  vitamin  D. 

It  must  be  remembered  that  the  fundamental  defect  in  rickets  is  not 
in  the  bone.  It  has  been  shown  that  slices  of  rachitic  bone  and  cartilage 
become  calcified  when  placed  in  normal  blood  senmi.  The  primary  fault 
in  rickets  resides  in  the  body  fluids,  which  do  not  make  bone  salts  avail- 
able to  the  bone.  The  action  of  vitamin  D  is  to  bring  about  alteration  of 
the  calcium  and  phosphorus  in  the  body  fluids  so  that  they  may  be  avail- 
able to  the  bone.  It  has'been  suggested  recently  that  vitamin  E)  probably 
does  not  exert  its  therapeutic  effects  through  improvement  in  intestinal 
absorption  of  phosphorus  but  rather  by  intensification  of  phosphorus 
turnover  in  bone.  This  results  in  hyperphosphatemia  and  a  decreased 
visceral  phosphorus  turnover^^ 

Human  Requirement 

The  exact  human  requirements  for  vitamin  D  are  unknown.  The 
requirement  of  vitamin  D  varies  greatly  among  individuals  and  among 
persons  of  various  ages.  Since  the  average  diet  furnishes  so  little  vitamin 
D,  it  must  be  assumed  either  that  the  requirement  of  vitamin  D  for  man 
is  extremely  low  or  that  his  needs  usually  are  provided  by  exposure  to 
sunshine.  The  requirement  of  vitamin  D  during  adult  life  has  not  been 
determined,  but  undoubtedly  the  vitamin  is  necessary  for  older  children 
and  for  adult  persons.  The  minimal  amounts  recommended  for  infants 

Vol.  I.  948 


452(14)  \  ITAAIINS  AND  VITAMIN  DEFICIENCY 

should  be  sufficient  for  those  of  this  age  group.  During  pregnancy  and 
lactation  and  for  children  less  than  a  year  old  400  to  800  international 
units  of  vitamin  D  constitute  the  daily  requirement  as  recommended  by 
the  Food  and  Nutrition  Board  of  the  National  Research  Council.  In 
administering  antirachitic  agents,  as  emphasized  previously  in  this  chap- 
ter, the  physician  should  think  in  terms  of  units  of  vitamin  D,  since  this 
is  the  only  way  in  which  the  doses  of  the  various  substances  containing 
vitamin  D,  which  differ  greatly  in  volume,  can  be  reduced  to  a  common 
denominator. 

Methods  for  Measurement  of  Vitamin  D 

When  almost  pure,  crystalline  vitamin  D  is  used,  it  can  be  deter- 
mined by  measurement  of  the  characteristic  absorption  spectrum  in 
the  ultraviolet.  There  is  no  chemical  method  by  which  the  presence  or 
amount  of  vitamins  D  can  be  determined  accurately.  Two  methods  gen- 
erally are  employed  for  the  biological  assay  of  vitamin  Ds.  A  simple  and 
convenient  method^"  which  concerns  the  growth  response  of  chicks  has 
been  described  recently. 

Clinically  roentgenological  examination  of  the  bones  of  the  forearm 
and  wrist  is  recommended  both  for  the  diagnosis  of  rickets  and  for  deter- 
mining the  healing  process.  Determination  of  the  amounts  of  calcium 
and  phosphorus  in  the  blood  also  may  be  helpful  in  following  the  course 
of  rickets  in  human  beings.  According  to  some  recent  reports  phospha- 
tase activity  is  a  valuable  and  probably  the  most  sensitive  index  of  active 
rickets". 

Toxicity 

V^hen  extremely  large  doses  of  vitamin  D  are  administered  to  animal 
or  man,  certain  pathological  changes  are  noted^^'^^  Hypervitaminosis  D 
is  an  exas^gerated  form  of  the  physiological  effect  of  the  vitamin.  The 
concentration  of  calcium  and  phosphorus  in  the  serum  is  increased,  and 
calcification  occurs  at  an  increased  rate.  Metastatic  calcification  may 
occur  in  the  renal  tubules,  heart,  blood  vessels,  bronchi  and  stomach^^ 
In  advanced  degrees  of  hypervitaminosis  D  resorption  of  bone  is  the 
most  prominent  feature^'.  The  animals  lose  weight  rapidly,  an  intense 
diarrhea  develops,  and  death  occurs  in  5  to  14  days.  If  smaller  doses  are 
administered,  the  animal  may  survive  and  the  described  lesions  will 
remain  for  at  least  6  months.  Diets  low  in  calcium  and  phosphorus  may 
prevent  the  calcification  process,  but  the  degenerative  changes  occur. 
Vol.  I.  948 


VITAMINS  D:  TOXICITY 


452(15) 


Some  adult  persons  treated  with  large  doses  of  vitamin  D  may  com- 
plain of  nausea,  headache,  diarrhea,  anorexia,  urinary  frequency  or  lassi- 
tude. Adults  treated  with  large  doses  of  vitamin  D  for  arthritis  have 
exhibited  various  manifestations  of  toxicity;  the  susceptibility  of  an  indi- 
vidual will  vary  at  different  times^''■^^  Danowski  and  his  associates*^  have 
reported  two  instances  of  dangerous  complications  resulting  from  the 
promiscuous  and  protracted  treatment  of  arthritis  with  large  quantities 
of  vitamin  D  without  medical  supervision.  The  patients  concerned  took 
from  150,000  to  500,000  international  units  daily  for  6  years  in  one  case 


Fig.  10.  Florid  rickets  in  young  twins  (a)  and  (b),  illustrating  deformities,  wide, 
irregular  epiphyseal  lines  and  characteristic  cupping  of  the  nietaphyses.  (By  courtesy 
of  Department  of  Pediatrics,  JVIayo  Clinic.) 

and  for  1 3  months  in  the  other.  Both  patients  experienced  osteoporosis, 
anemia,  elevated  values  for  blood  nonprotein  nitrogen,  hypercalcemia 
and  albuminuria.  Extensive  deposits  of  calcium  in  the  soft  tissue  devel- 
oped in  one  patient.  One  had  hypertension  with  retinal  vascular  changes. 
After  the  administration  of  vitamin  D  had  been  discontinued,  there  was 
gradual  clinical  improvement  in  these  two  patients.  However,  no  serious 
toxic  effects  have  been  reported  in  cases  in  which  doses  up  to  1,000,000 
units  have  been  administered  to  rachitic  children. 

In  spite  of  the  aforementioned  possible  effects,  the  physician  need 

Vol.  1.  948 


452 (i6)  VITAMINS  AND  VITAMIN  DEFICIENCY 

not,  in  general,  fear  toxicity  as  an  effect  of  vitamin  D.  If  renal  insuffi- 
ciencv  exists,  the  physician  should  use  caution;  repeated  urinalyses  should 
be  conducted  while  vitamin  D  therapy  is  being  employed. 

Diagnosis  of  Vitamin  D  Deficiency 

Althousfh  some  report  that  the  incidence  of  undiagnosed  rickets  in 
certain  sections  of  the  United  States  may  be  as  high  as  75  per  cent.,  yet 
the  presence  of  this  disease  is  extremely  difficult  to  determine  with  rea- 
sonable certainty  except  when  the  condition  is  severe.  Several  recent 
reports  tend  to  affirm  this  fact^^  The  clinical  diagnosis  hinges  on  the 
finding  of  the  various  deformities  described  in  the  consideration  of  the 
pathological  changes.  Among  the  more  important  of  these  are  craniotabes 
and  the  rachitic  rosar)^  In  the  early  or  mild  stage  the  physician  may 
encounter  difficulty  in  distinguishing  this  condition  from  the  normal 
softness  of  the  baby's  skull.  The  rachitic  rosary  is  one  of  the  most  con- 
stant signs  of  rickets,  but  much  skill  is  required  to  distinguish  it  from 
the  normal  enlargement  of  the  costochondral  junction.  An  enlarged 
fontanelle  may  be  evidence  of  rickets,  but  in  many  cases  there  is  pre- 
mature closure.  Bowlegs  (Fig.  10^  and  b)  and  deformities  of  the  thorax, 
chicken  breast  and  funnel  breast,  Harrison's  groove,  are  of  common 
occurrence,  but  their  presence  alone  is  not  pathognomonic,  since  they 
occur  also  in  many  other  conditions. 

To  one  acquainted  with  the  intricacies  of  this  sort  of  diagnosis  the 
roentgenogram  offers  invaluable  aid  in  the  recognition  of  rickets,  but 
there  are  many  pitfalls  in  differential  diagnosis.  A  description  of  the 
changes  revealed  by  the  roentgenogram  (Fig.  11)  is  out  of  place  here; 
the  reader  can  find  them  in  textbooks  of  radiology.  Since  rickets  is  not 
primarily  a  disease  of  bone,  roentgenological  evidence  may  be  lacking 
early  in  the  course  of  the  disease. 

The  concentration  of  calcium  and  phosphorus  in  the  serum  usually 
is  altered  in  the  presence  of  rickets.  The  concentration  of  inorganic 
phosphate  is  more  constantly  lower  than  that  of  calcium;  the  product 
of  the  concentration  of  these  two  minerals  is  of  more  constant  value. 
In  the  acute  stage  of  deficiency  of  vitamin  D  there  is  an  elevation  in 
serum  phosphatase.  With  few  exceptions  this  appears  to  be  a  satisfactory 
measure  for  the  detection  of  early  acute  rickets^". 

Rachitic  tetany  also  is  a  derangement  in  calcium  and  phosphorus 
metabolism  which  results  from  deficiency  of  vitamin  D.  The  latent  and 
manifest  forms  are  the  two  types  of  infantile  tetany  encountered  clin- 

Vol.  I.  948 


VITAMINS  D:  DIAGNOSIS  452(1?) 

ically.  In  the  fomier  there  are  no  apparent  symptoms,  and  the  hyper- 
irritabihtv  of  the  nervous  system  must  be  elicited  by  artificial  excitation 
of  the  peripheral  nerves.  The  manifest  form  gives  rise  to  tonic  states  and 
generalized  convulsions. 

The  most  reliable  and  delicate  sign  in  the  diagnosis  of  latent  tetany 
is  Erb's  phenomenon.  A  galvanic  current  is  employed  to  distinguish  irri- 


Fig.  II.  Late  rickets  in  a  thirteen-year-old  child,  both  hands  showing  the  deformi- 
ties, wide,  irregular  epiphyseal  lines  and  characteristic  cupping.  (By  courtesy  of 
Department  of  Pediatrics,  Alayo  Clinic.) 

tability  of  the  nervous  system.  The  Chvostek  sign  is  another  rather 
reliable  method  of  diagnosis.  The  Trousseau  phenomenon  is  described 
often  as  diagnostic  of  infantile  tetany,  but  it  probably  is  not  so  reliable 
as  the  other  two  mentioned.  Among  laboratory  observations  the  presence 
of  a  low  concentration  of  serum  calcium  is  of  extreme  importance  in  the 
diagnosis  of  tetany.  In  latent  tetany  the  value  for  the  serum  calcium 
\'oi..  I.  948 


452(i8)  VITAMINS  AND  VITAiMIN  DEFICIENCY 

usually  is  in  the  neighborhood  of  7  to  8  mgni.  per  100  c.c,  and  it  may 
decrease  to  5  to  6  mgni.  in  cases  of  manifest  tetany. 

The  outstanding  manifestations  of  tetany  are  the  typical  carpopedal 
spasms,  the  characteristic  "tetany  facies",  laryngospasm  and  of  course, 
the  convulsive  seizures.  The  diagnosis  of  manifest  rachitic  tetany  is,  as  a 
rule,  not  difficult.  In  the  differential  diagnosis  the  physician  must  con- 
sider laryngitis,  congenital  laryngeal  stridor,  nervous  holding  of  the 
breath  and  meningitis. 

In  osteomalacia  as  in  rickets  the  essential  abnormality  is  deficient 
calcification  of  the  osteoid  tissue.  It  is  seen  occasionally  in  men,  but  is 
encountered  most  often  in  women,  especially  among  those  who  are  preg- 
nant. Usually  numerous  causative  factors  are  operative  in  any  single  case 
of  osteomalacia,  but  in  all  cases  there  is  presumably  a  deficiency  of  vita- 
min D.  In  most  cases  osteomalacia  as  observed  in  the  United  States  is 
associated  with  chronic  steatorrhea.  As  a  result  of  the  faulty  digestion 
and  absorption  of  fat,  insoluble  calcium  salts  are  formed,  and  the  fat- 
soluble  vitamin  D  is  excreted  in  the  excess  fat.  This  has  been  well  demon- 
strated by  various  investigations  carried  out  in  cases  of  osteomalacia. 

In  the  mild  form  of  osteomalacia  the  patient  may  complain  only  of 
weakness  or  of  pains  in  the  bones  of  the  legs  or  in  the  lower  part  of  the 
back  while  standing  or  walking.  In  cases  of  severe  osteomalacia  the 
patient  may  seek  medical  aid  because  of  the  distressing  symptoms  of 
severe  tetany.  Another  patient  may  suffer  from  a  crushed  vertebra  re- 
sulting from  moderate  lifting  or  a  minor  fall.  In  cases  of  advanced  disease 
severe  backache  is  the  most  common  symptom.  This  pain  is  aching  in 
character,  often  is  generalized  and  is  worse  in  the  winter,  when  there  is 
[greater  deficiency  of  vitamin  D  than  at  other  times.  Muscular  weakness 
may  be  marked,  and  a  waddling  gait  is  not  uncommon.  Often  there  is 
marked  sensitivity  of  the  bones  to  light  pressure.  The  skeletal  deformities 
are  numerous.  In  the  roentgenogram  generalized  osteoporosis,  thinning 
of  the  cortices,  bowing,  fractures  and  deformities  of  various  types  are 
evident. 

The  diagnosis  of  osteomalacia  is  not  particularly  difficult,  if  the  phy- 
sician suspects  its  presence.  Tetany,  occurring  in  association  with  chronic 
diarrhea,  or  a  calcium-phosphorus  deficiency  always  should  suggest 
osteomalacia.  Any  skeletal  disease  characterized  by  generalized  decalcifi- 
cation, such  as  the  osteoporotic  forms  of  hyperparathyroidism,  senile 
osteoporosis  and  the  like,  may  be  mistaken  for  osteomalacia.  The  treat- 
ment of  osteomalacia  is  essentially  the  same  as  the  treatment  of  rickets. 

Vol.  I.  948 


VITAMINS  D:  TREATMENT 
Treatment  of  \'itamin  D  Deficiency 


452(19) 


Of  primary  importance  in  the  treatment  of  rickets  is  the  promotion 
of  heahng  of  the  lesion  as  rapidly  as  possible.  The  dose  suggested  as  a 
preventive,  although  it  is  actually  capable  of  effecting  cure  in  simple 


'  Fig.  12.  Late  rickets  in  a  tliirrccn-xcar-oKl  child.  On  the  left  (.r)  before  treatment 
\\ith  approximately  1,000.000  units  of  vitamin  D  daily  in  the  form  of  activated  crgosrcrol, 
(The  activated  ergosterol  is  not  on  the  market  but  was  used  experimentally.  It  was 
supplied  bv  the  Mead,  Johnson  and  Company);  (h)  after  treatment,  some  five  months 
later.    (By  courtesy  of  Department  of  Pediatrics,  Mayo  Clinic.) 

rickets,  brings  about  this  cure  too  slowly.  A  dose  of  1,000  U.S.P.  units, 
3  teaspoonfuls  of  cod  liver  oil,  daily  will  control  advanced  rickets  in  most 
cases  in  3  to  4  weeks.  For  premature  infants  often  it  is  necessary  to  ad- 
minister 10,000  to  20,000  U.S.P.  units  daily  to  effect  a  cure,  and  the 
condition  of  some  infants  is  so  refractory  to  treatment  as  to  require 
60,000  units  daily.  Once  the  disturbance  has  been  brought  under  control, 
as  evidenced  bv  detemiinations  of  blood  calcium  and  phosphorus  or  bv 
^'oI..  I.  948 


452(20)  VITAA4INS  AND  VITAAIIN  DEFICIENCY 

roentcrenolocrical  examinations,  the  dose  of  vitamin  D  can  be  reduced 
to  a  preventive  level.  In  cases  in  which  older  children  are  hypersiis- 
ceptible  to  rickets,  it  may  be  necessary  to  continue  the  administration  of 
large  doses;  the  increased  requirements  of  the  premature  infant  usually 
are  transitory. 

The  treatment  of  active  rickets  with  large,  single  doses  of  vitamin  D 
administered  parenterally  has  received  considerable  attention  during  the 
past  few  years^^"^\  Administration  of  500,000  to  1,000,000  U.S. P.  units 
of  vitamin  D  to  children  who  had  rickets,  including  premature  infants, 
has  been  followed  by  rapid  healing  without  clinical  evidence  of  toxicitv 
(Fig.  12).  In  these  cases  the  value  for  serum  phosphatase  may  become 
normal  as  early  as  the  fifth  or  sixth  day,  and  roentgenographical  evidence 
of  healing  also  may  be  noted. 

iMany  have  believed  that  infants  can  be  protected  successfully  from 
rickets  for  the  whole  of  one  winter  by  the  ingestion  of  a  single  large  dose 
of  vitamin  D.  Recently  Krestin^^  made  a  clinical  trial  of  the  procedure, 
using  full-term  infants  and  children  from  2  months  to  3  years  of  age, 
who  shewed  no  radiological  or  clinical  evidence  of  rickets.  On  the  basis 
of  results  of  his  study,  he  suggested  that,  when  a  child  is  first  seen  in  late 
winter  or  spring,  one  dose  of  7.5  mgm.  of  calciferol,  vitamin  D2,  having 
an  activity  of  300,000  international  units,  probably  is  sufficient  for  pro- 
tection until  the  next  winter.  When  the  child  is  seen  for  the  first  time  in 
fall  or  early  winter,  the  dose  should  be  repeated  after  three  months.  For 
premature  infants  and  those  recovering  from  marasmus  or  acute  illnesses 
larger  and  more  frequently  administered  doses  may  be  necessary. 

There  are  occasional  cases  in  which  rickets  does  not  respond  to  treat- 
ment with  the  usual  amounts  of  vitamin  D^^-".  In  some  cases  rickets  is 
due  to  a  disturbance  of  the  acid-base  balance  and  has  been  treated  suc- 
cessfully by  the  administration  of  sodium  bicarbonate  or  by  the  use  of 
massive  doses  of  vitamin  D.  The  quantity  of  vitamin  D  needed  may  be 
so  large  that  it  approaches  dosages  that  are  definitely  toxic.  AMiile  the 
maintenance  dose  is  being  established,  it  is  desirable  to  examine  the  urine 
every  i  to  3  days  for  albumin,  erythrocytes  and  calcium  casts.  The  blood 
calcium  should  be  determined  weekly  and  should  not  be  allowed  to  rise 
above  12  mgm.  per  100  c.c,  if  the  dosage  exceeds  20,000  units  daily  for 
an  infant  or  50,000  units  for  a  child.  Administration  of  the  vitamin  should 
be  discontinued,  if  anorexia  or  nausea  appears. 

In  the  treatment  of  rachitic  tetany  it  is  important  that  the  effects  be 
produced  rapidly.  It  has  been  pointed  out  that  the  primary  derangement 
in  tetany  is  in  the  concentration  of  serum  calcium,  and  it  is  necessary 

\'0L.  I.  948 


VITAAIINS  D.   TREATiMENT  452(21) 

that  this  be  remedied  rapidly  by  the  administration  of  calcium  salts.  The 
usual  method  is  to  administer  3  or  4  gm.  of  calcium  chloride  intra- 
venously as  an  initial  dose.  This  should  be  followed  by  a  dose  of  i  gm. 
4  times  daily  for  2  or  3  days,  and  then  by  i  gm.  twice  a  day  for  5  to  7 
days.  In  the  administration  of  vitamin  D  a  program  similar  to  that  de- 
scribed for  the  treatment  of  rickets  may  be  followed. 

Having  made  a  diagnosis  of  rickets,  determined  which  method  of 
treatment  to  use  and  used  it,  the  physician  now  is  confronted  with  the 
problem  of  how  to  ascertain  if  this  therapy  is  accomplishinor  the  desired 
results.  The  best  way  to  do  this  is  to  determine  the  concentration  of  cal- 
cium and  phosphorus  in  the  serum.  If  the  concentration  of  calcium  is 
within  normal  limits,  and  the  concentration  of  inorganic  phosphate  rises 
to  5  mgm.  per  100  c.c,  vitamin  D  therapy  is  succeeding.  In  ordinary^ 
cases,  in  which  the  usual  doses  are  administered,  the  concentration  of  the 
serum  phosphates  may  be  expected  to  reach  normal  on  about  the  tenth 
day  of  treatment.  In  the  absence  of  chemical  and  roentgenological  exam- 
inations appraisal  of  treatment  becomes  very  difficult;  bony  deformities 
disappear  very  slowly.  Perhaps  the  best  clinical  indication  that  therapy 
with  vitamin  D  is  succeeding  is  improvement  in  muscle  function  as  evi- 
denced by  efforts  on  the  part  of  the  child  to  walk  or  to  sit  up.  He  seems 
to  gain  strength  and  becomes  more  active.  The  bony  deformities  gradu- 
ally disappear,  and  the  bones  acquire  an  increased  degree  of  rigidity. 

Methods  of  preventing  the  occurrence  of  rickets  should  be  common 
knowledge  to  every  physician.  For  preventive  measures  the  importance 
of  commencing  administration  of  the  vitamin  early  and  reaching  the  full 
dose  by  the  end  of  the  second  month  of  the  infant's  life  cannot  be  re- 
peated too  often^^  It  is  best  to  begin  with  a  dose  of  a  half  teaspoonful. 
2  c.c,  of  cod  liver  oil,  175  units;  after  a  few  days  this  may  be  increased 
to  I  teaspoonful,  4  c.c.  or  350  units,  and  in  the  next  2  weeks  raised  to  2 
teaspoonfuls,  8  c.c.  or  700  units.  Use  of  this  dose  should  be  continued 
until  the  child  is  2  years  of  age.  If  there  is  any  reason  to  suspect  that  the 
child  may  be  susceptible  to  rickets,  the  dose  should  be  increased  during 
the  first  year  so  as  to  supply  1,000  units  of  vitamin  D  daily. 

Irradiated  milk  does  not  exhibit  sufficient  potency  in  vitamin  D  for 
the  prevention  of  rickets  in  cases  in  which  a  susceptibility  exists.  Sunlig^ht 
may  be  relied  on  for  the  prevention  of  rickets  in  the  summer  months,  but 
in  the  winter  for  all  practical  purposes  the  rays  of  the  sun  may  be  re- 
garded as  devoid  of  antirachitic  rays. 


\^)i..  I.  948 


452(22)  VITAMINS  AND  VITAMIN  DEFICIENCY 

VITAMIN  E 
Chemistry 

As  early  as  1922  a  new  factor,  most  abundantly  present  in  wheat- 
germ  oil,  was  demonstrated  as  needed  in  the  rat  for  the  successful  com- 
pletion of  pregnancy  in  the  female  and  for  continued  fertility  in  the 
male.  In  1936  this  factor  was  identified  successfully  as  alpha  tocopherol 
(Evans,  Emerson  and  Emerson)'".  Femholz'"  in  1938  proposed  the 
formula  for  alpha  tocopherol  on  the  basis  of  oxidative  degradation  with 
chromic  acid,  and  synthesis  was  accomplished  later  independently  in 
three  laboratories"  (Fig.  13). 

Three  factors  have  been  isolated  from  natural  material,  namely, 
alpha,  beta  and  gamma  tocopherol.  Beta  tocopherol  and  gamma  tocoph- 
erol are  homologues  of  the  natural  substance  and  have  almost  identical 
properties  but  slightly  less  biological  activity.  Natural  gamma  tocopherol 


Fig.  13.    Structural  formula  for  alpha  tocopherol. 

is  approximately  50  per  cent,  more  potent  than  synthetic  dl-gamma- 
tocopherol,  and  natural  beta  tocopherol  is  about  100  per  cent,  more 
active  than  synthetic  dl-beta-tocopherol"-.  These  substances  are  readily 
soluble  in  lipid  solvents  but  are  only  slightly  soluble  in  water.  Although 
stable  at  high  temperatures  (200°  C.),  they  rapidly  lose  their  activity  in 
the  presence  of  ultraviolet  light  or  mild  oxidizing  agents.  The  long- 
recognized  resistance  to  rancidity  of  vegetable  oil  that  contains  vitamin 
E  might  be  cited  as  an  everyday  example  of  its  oxidation-inhibiting 
quality. 

There  are  numerous  compounds  related  to  the  tocopherols,  which 
have  been  shown  to  exhibit  vitamin  E  activity,  but  they  do  so  in  a  limited 
manner  when  compared  to  tocopherol.  Of  some  special  interest  is 
naphtho-tocopherol,  which  shows  vitamin  E  activity  in  25  mgm.  doses 
but  also  shoM's  vitamin  K  activity  in  doses  of  from  300  to  600  gamma**'^. 
The  tocopherols  themselves  have  a  certain  structural  specificity,  and  the 
removal  of  a  methyl  group  from  the  aromatic  nucleus  or  the  aliphatic 
side  chain  greatly  diminishes  the  vitamin  V,  activity  of  the  substances. 
The  acetate  of  tocopherol  is  equal  in  biological  activity  and  possesses  the 

Vol.  I.  948 


VITAMIN  E:  PHYSIOLOGY  AND  PATHOLOGY     452(23) 

added  advantage  of  increased  stability  over  that  of  tocopherol.  It  has 
been  suggested  that  synthetic  raceniic  tocopherol,  tocophervl  acetate,  be 
made  the  international  standard  for  vitamin  E,  and  the  suggestion  has 
been  adopted.  The  international  unit  is  the  vitamin  L  activity  of  i.o 
mgm.  of  the  standard  preparation,  racemic  tocopherol  acetate  in  olive 
oil.  The  quantity  represents  the  average  amount  which  prevents  resorp- 
tion gestation  in  rats  deprived  of  vitamin  E  when  the  substance  is  admin- 
istered orally*^^*^''. 

Physiology  and  Pathology 

These  fat-soluble  vitamins  E  and  their  esters  are  in  the  presence  of 
bile  acids  easily  absorbed  from  the  intestinal  tract'''^  and  on  intake  of  esters 
the  free  vitamin  appears  in  the  blood.  Excess  doses  cause  the  excretion  of 
a  certain  amount  in  the  feces,  but  only  traces  are  found  in  the  urine.  This 
suggests  that  the  vitamin  is  inactivated  in  the  organism,  probabU'  by  an 
oxidation  mechanism.  These  vitamins  are  stored  in  very  small  amounts 
in  animal  body  fats,  in  the  muscles  and  in  the  anterior  lobe  of  the  pitui- 
tary gland. 

In  animals  a  lack  of  vitamin  E  manifests  itself  chiefly  by  changes  in 
the  reproductive  mechanism;  it  was  on  the  basis  of  this  observation  that 
the  terms  "antisterility  vitamin"  and  "reproductive  vitamin"  wer.e  de- 
rived. In  the  presence  of  vitamin  E  deficiency  conception  occurs  in  the 
female  rat,  but  it  is  followed  by  "resorptive  sterility".  In  the  male  rat 
degeneration  of  the  germinal  epithelium  and  spermatozoa  develops  to  the 
point  of  complete  loss  of  reproductive  power. 

For  a  number  of  years  interest  was  centered  exclusively  on  the  role 
which  this  vitamin  played  in  reproduction.  It  seems  that  such  an  action 
was  too  narrow  a  definition  of  its  function.  In  the  absence  of  vitamin  E 
in  the  diet  of  many  animals  muscular  dystrophy  and  a  characteristic 
paralysis  of  the  hindquarters  have  been  shown  to  develop""-  ^^-  *^^.  Although 
vitamin  E  appears  essential  for  the  integrity  of  the  skeletal  muscle  of 
many  species,  the  relationship  of  these  disturbances  to  human  muscular 
dystrophies  is  by  no  means  clear.  It  has  been  suggested  that  it  is  con- 
cerned in  some  way  with  the  contractile  phase,  and  increased  oxyo-en 
uptake  in  the  muscle  tissue  has  been  observed  duringr  vitamin  E  defi- 
ciency'^  This  possible  relationship  to  human  muscular  disturbances  re- 
mains an  inviting  subject  for  further  investigation. 

Recently  another  activity  of  vitamin  E  has  been  recoijnized.  In  a 
series  of  studies  Hickman  and  associates'^'  '-■ '"'  have  shown  that  natural 

Vol.  I.  948 


452(24)  VITAA1TNS  AND  VITAMIN  DEFICIENCY 

vitamin  E  enhances  the  growth-promoting  power  of  vitamin  A  alcohol 
and  vitamin  A  acetate.  The  vitamin  A  activity  of  carotene  is  markedly 
influenced  also  by  the  intake  of  tocopherol.  It  is  suggested  that  this  spar- 
ing action  on  the  A  vitamins  is  due  chiefly  to  repression  of  oxidation  in 
or  near  the  gastrointestinal  tract.  Recently  it  has  been  shown  also  that 
tocopherol  increases  both  the  storage  of  vitamin  A  in  the  liver  and  the 
stability  of  carotene  in  the  intestinal  tract.  It  appears  that  the  role  of 
tocopherol  as  an  intestinal  antioxidant  has  been  established^^ 

We  have  no  exact  knowledge  of  the  quantitative  requirements  of 
man  for  vitamin  E.  We  lack  also  precise  assays  of  the  vitamin  E  content 
of  foodstuffs.  Apparently  vitamin  E  occurs  in  most  foods,  and  it  is  note- 
worthy that  one  of  the  greatest  obstacles,  \\^hich  investigators  encoun- 
tered, was  in  obtaining  a  diet  deficient  in  this  vitamin.  Wheat-germ  oil  is 
the  richest  source  of  vitamin  E,  but  also  it  is  found  in  considerable 
amounts  in  cottonseed  oil,  lettuce  oil,  rice-germ  oil  and  other  seed-germ 
oils. 

Various  authors  have  used  wheat-germ  oil  in  doses  varying  from  0.25 
c.c.  to  6  c.c.  daily,  and  it  may  be  of  significance  that  any  apparent  success 
was  the  same  in  spite  of  any  variation  in  the  dose  used.  Toxic  reactions 
have  not  been  reported  in  cases,  in  which  small  doses  were  administered, 
and  large  doses  of  wheat-germ  oil  have  given  rise  to  only  minor  symp- 
toms. The  danger  of  production  of  neoplasms  by  the  use  of  such  oil 
appears  to  be  nonexistent. 

A  chemical  method  for  the  determination  of  tocopherols  in  blood 
plasma  has  been  described"',  and  in  a  small  series  of  cases  values  for  toco- 
pherol in  human  normal  plasma  were  found  to  average  1.20  mgm.  per 
100  c.c. 

Clinical  Use  of  \^itamin  E 

Whether  or  not  avitaminoses  occur  in  man  has  not  yet  been  defi- 
nitely decided.  Vitamin  E  has  been  used  in  the  treatment  of  many  clinical 
ills,  but  to  date  justifiable  conclusions  have  been  difficult  to  make. 

There  is  some  evidence  to  support  the  view  that  vitamin  E  may  exert 
a  beneficial  influence  in  certain  cases  of  habitual  abortion'*',  threatened 
abortion  and  abruptio  placentae.  In  the  presence  of  male  and  female 
sterility,  menstrual  disturbances,  the  toxemias  of  pregnancy,  faulty  lacta- 
tion and  vaginal  pruritus  the  reported  results  are  at  variance  and  cannot 
be  accepted  until  further  evidence  has  accumulated. 

In  the  treatment  of  human  myoneurogenic  disturbances  with  vitamin 

Vol.  I.  948 


VITAMIN  E:  CLINICAL  USE  452(25) 

E  the  results  have  been  most  discouraging.  Recently,  however,  Alilhorat 
and  Bartels"  have  suggested  that  tocopherol  forms  a  condensation  prod- 
uct with  inositol  in  the  gastrointestinal  tract,  and  that  the  inherited  defect 
in  muscular  dystrophy  is  a  deficiency  in  this  reaction  of  condensation. 
These  and  other  more  recent  suggestions  stimulate  hope  that  vitamin  E 
is  a  factor  to  be  reckoned  with  in  human  physiology  and  perhaps  in 
human  disease^^. 


Vol..  I.  948 


452(26)  VITAMINS  AND  VITAMIN  DEFICIENCY 

VITAMINS  K 

The  introduction  of  vitamin  K  in  clinical  medicine  came  as  a  result 
of  an  observation  of  Dam  and  his  associates'''"'  of  Copenhagen,  Den- 
mark. They  showed  that  a  deficiency  disease  could  be  produced  in 
chicks  subsisting  on  feed  A\'ashed  in  ether  and  could  be  cured  .by  the 
administration  of  an  antihemorrhagic  material  present  in  hog  liver  fat, 
hemp  seed  and  certain  cereals  and  vegetables.  Later  it  was  shown  by 
these  investigators  that  deficiency  in  this  dietary  factor  resulted  in  dimi- 
nuition  in  the  amount  of  prothrombin  in  the  circulating  blood,  \^'hich  led 
to  fatal  hemorrhagic  diathesis.  The  term  "vitamin  K"  was  proposed  by 
Dam  as  an  abbreviation  of  the  name  "Koagulations  Vitamin"  to  apply 
to  the  substance  that  Mas  necessary  for  the  prevention  of  a  nutritional 
deficiency  disease  in  chicks.  Soon  it  was  suggested  by  Quick  of  the 
United  States  that  deficiency  of  vitamin  K  mifi^ht  be  present  in  patients 
who  had  obstructive  jaundice.  These  suggestions  now  have  been  con- 
firmed amply  and  extended,  and  within  a  relatively  short  time  various 
workers  in  this  country  and  abroad'"^*'  have  demonstrated  that  vitamin 
K  under  most  circumstances  is  a  specific  remedy  for  deficiency  of 
prothrombin. 

Chemistry 

In  1939  McKee  and  his  associates  reported  the  isolation  of  vitamin  Ki 
from  alfalfa  and  of  vitamin  K2  from  putrefied  fish  meal  and  presented 

H         o 

I         II 
.c,         c 


H-C  C  C^ 


v^/    \^/        C-C=C-C--C-C-C-C--C-C-C-CHj 

^        'r       I       /iii/iiii 

^  ^  H         CHj   H      \H      H  CH3  H/^   H     H     CHj 

Fig.  14.     Tlie    .strucrur;il    lonmihi    of    viramin    Ki     ( 2-nictli\l-^-phvtvl-i,4-naphtho- 
(juinone). 

evidence  to  indicate  a  quinoid  structure  of  these  vitamins.  For  the  final 
isolation  and  synthesis  of  vitamin  Ki  Doisey  and  his  associates,  Almquist 
and  Klose,  Fieser  and  his  associates.  Dam,  Karrer  and  co-workers  are  re- 
sponsible. Independently  these  groups  of  investigators  reported  the 
structure  of  the  viramin  Ki  molecule  to  be  2-merhyl-3-phyryl-i,  4- 
naphrhoquinone  (Fig.  14).  This  vitamin  is  identical  with  z-methyl-i. 
Vol.  I.  948 


VITAMINS  K:  CHEMISTRY  452(27) 

4-naphthoqninone  with  the  exception  that  vitamin  Ki  has  a  phytyl  side 
chain  in  the  three  position.  The  synthetic  product  also  is  identical  with 
natural  vitamin  Ki,  which  is  obtained  from  alfalfa.  Exposure  to  sunlight 
destroys  the  vitamin  activity  of  alfalfa  within  several  hours,  although, 
if  artificial  light  is  used,  little  destruction  is  observed  within  24  hours. 
The  pure  preparations,  however,  are  destroyed  by  both  sunlight  and 
artificial  light.  Under  ultraviolet  light  rays  the  oxide  of  vitamin  Ki  is 
about  3  times  as  stable  as  vitamin  Ki  but  has  the  same  clinical  effect  as 
vitamin  Ki.^*'  A  large  part  of  the  activity  of  concentrates  of  vitamin  K 
is  destroyed  by  alkali,  by  strong  acids  and  by  aluminum  chloride.  The 
vitamin  is  fat  soluble  and  at  low  temperatures  forms  yellow  crystals. 

Vitamin  K2  is  another  natural  vitamin  K  and  was  isolated  first  from 
putrefied  fish  meal.  The  structure  of  this  vitamin  still  is  under  discussion. 
Some  investigators  believe  the  probable  structural  formula  is  2 -methyl- 3 - 
difamesyl-i,  4-naphthoquinone  with  an  empiric  formula  C41H56O2.  This 
compound  is  also  fat-soluble  and  has  been  obtained  as  light  yellow, 
crystalline  flakes. 

The  demonstration  of  the  quinoid  structure  of  the  vitamins  K  has 
stimulated  grreat  study  of  the  many  substances  which  possess  a  quinoid 
nucleus.  The  first  report  of  a  synthetic  compound  having  antihemor- 
rhagic  activity  was  made  by  Almquist  and  Klose,  who  found  that  phthi- 
ocol  (2-metl-ivl-3-hydroxy-i,  4-naphthoquinone)  possesses  marked 
antihemorrhagic  activity,  but  that  it  is  only  1/500  as  active  as  vitamin 
Ki.  Phthiocol  is  the  yellow  pigment  found  in  the  human  tubercle  bacil- 
lus. Of  all  the  naphthoquinone  derivatives  studied  2-methyl-i,  4-naphtho- 
quinone has  proved  to  be  the  most  active.  This  compound  can  be  syn- 
thesized by  the  oxidation  of  2 -methyl-naphthalene.  This  material  is  very 
sliq-htly  soluble  in  water.  In  solution  its  activity  is  impaired  by  steriliza- 
ticm  w'ith  steam;  therefore,  it  is  rather  unstable  unless  special  precautions 
are  taken.  This  compound  is  so  active  that  several  investigators  have 
sue^gested  that  it  be  adopted  as  a  basic  standard  for  assay  of  vitamin  K. 
By  some  assays  this  compound  has  been  found  to  be  about  three  times 
as  potent,  on  a  basis  of  weight,  as  vitamin  Ki.  Because  of  the  great  use- 
fulness of  this  compound  in  clinical  medicine  the  Council  on  Pharmacy 
and  Chemistry  of  the  American  Medical  Association  on  the  recom- 
mendation of  the  Committee  on  Nomenclature  authorized  the  use  of 
"menadione"  as  a  nonproprietary  name  for  this  substance^'. 

Many  other  compounds  have  been  tested  for  vitamin  K  activity.  Most 
of  those,  which  have  such  activity,  are  basically  i,  4-naphthoquinone 
or  the  corresponding  hydroquinone;  a  few,  however,  are  not.  The  com- 

VOL.  I.  948 


452(28)  VITAMINS  AND  VITAAilN  DEFICIENCY 

pounds,  4-amino-2 -methyl- 1 -naphthol  hydrochloride  and  2-methyl-i, 
4-naphthohydroquinone-3 -sodium  sulfonate,  are  water  soluble  and, 
therefore,  have  proved  to  be  of  considerable  use  clinically.  These  com- 
pounds are  not  so  active  as  2-methyl-i,  4-naphthoquinone,  but  they  are 
active  enough  to  produce  desired  clinical  results.  Apparently  these 
derivatives  of  the  simpler  quinones  are  utilized  more  efficiently  than  are 
the  corresponding  derivatives  of  the  natural  vitamins.  A  monosodium- 
bisulfite  of  menadione  has  been  given  the  nonproprietary  name  of 
"menadione  bisulfite";  it  is  also  an  active  water-soluble  derivative  of 
menadione^^ 

Physiology 

Many  investigators  have  shown  that  the  presence  of  bile  in  the  intes- 
tinal tract  is  essential  for  proper  absorption  of  the  fat-soluble  vitamin  K, 
and  there  is,  futhermore,  some  evidence  to  suggest  that  these  fat-soluble 
compounds  are  absorbed  better,  if  other  fats  are  present  in  the  intestinal 
tract.  Clinically  it  is  well  established  that  the  presence  of  bile,  or  more 
correctly,  the  presence  of  adequate  amounts  of  bile  salts,  is  required  for 
the  proper  absorption  of  vitamins  K.  The  exact  point  of  absorption  in 
the  intestinal  tract  is  not  known,  but  clinical  experience  indicates  that 
concentrates  of  vitamin  K  are  not  absorbed  throuirh  the  colon  or  upper 
part  of  the  ileum,  but  that  they  are  absorbed  readily  through  the  upper 
part  of  the  small  intestine.  Recently  it  has  been  reported  that  excessive 
amounts  of  liquid  petrolatum  administered  with  meals  may  prevent 
proper  absorption  of  this  vitamin. 

The  vitamin  is  not  stored  readily  in  the  body,  but  it  has  been  found 
in  the  livers  of  lower  animals  in,  relatively  small  amounts.  Greaves  has 
shown  that  in  the  liver  of  the  rat  vitamin  K  is  not  stored  in  appreciable 
amounts.  Results  of  clinical  \\^ork  would  indicate  that  the  same  obser- 
vations are  applicable  to  the  human  being.  In  so  far  as  is  known,  vitamin 
K  is  not  present  in  the  urine.  Ir-  can  be  demonstrated  in  the  feces,  but 
whether  it  is  there  because  the  feces  merely  hold  the  organisms  M'hich 
are  known  to  contain  vitamin  K,  or  whether  the  presence  of  the  vitamin 
in  feces  is  referable  to  real  excretion  of  vitamin  K,  remains  to  be  estab- 
lished. The  vitamin  is  not  present  in  human  bile  collected  under  sterile 
conditions.  In  chicks  subsisting  on  a  normal  diet  the  spleen,  red  muscle, 
S^izzard,  bone  marrow  and  pancreas  were  found  to  contain  relatively 
large  amounts  of  vitamin  K,  whereas  the  liver  and  lungs  were  found 
to  contain  somewhat  less. 

Vol.  T.  948 


VITAMINS  K:  PHYSIOLOGY  452(^9) 

It  has  been  shown  that  2 -methyl- 1,  4-naphthoquinone  is  bacterio- 
static and  bactericidal  for  both  gram-positive  cocci  and  gram-negative 
bacilli,  and  similar  effects  have  been  noted  in  the  case  of  many  fungi. 
The  mode  of  action  apparently  consists  of  the  blocking  of  essential  en- 
zymes through  combination  with  sulfhydryl  groups.  This  mode  of 
action  is  similar  to  that  suggested  by  other  investigators  for  several  anti- 
biotic agents,  including  penicillin*'^ 

Littfe  is  known  concerning  the  action  of  vitamin  K  in  the  animal 
organism.  It  has  been  well  demonstrated  that  this  vitamin  and  related 
compounds  have  some  relationship  to  the  blood-clotting  mechanism. 

Avitaminosis  K  produces  a  decrease  in  the  prothrombin  level  of  the 
blood,  which  increases  rapidly  after  the  administration  of  vitamin  K. 
Vitamin  K  does  not  fomi  a  part  of  the  prothrombin  molecule,  since 
orally  administered  prothrombin  does  not  show  vitamin  K  activity.  The 
manner  in  which  vitamin  K  participates  in  the  formation  of  prothrombin 
is  not  known.  It  has  been  suggested  that  vitamin  K  is  a  reversible  oxida- 
tion-reduction catalyst,  the  hydroquinone  form  of  which  is  oxidized 
readily  by  molecular  oxygen.  This  reversible  character  of  the  vitamin 
may  be  used  to  explain  the  fact  that  small  quantities  produce  the  charac- 
teristic effect"". 

More  recently  a  hypothesis  has  been  reported,  which  suggests  that 
the  antihemorrhagic  effect  of  vitamin  K  and  its  synthetic  analogues  is 
due  to  biochemical  degradation  to  phthalic  acid,  and  that  it  is  largely 
a  function  of  their  capacity  to  be  transformed  into  the  latter"^  The 
authors"',  who  advanced  such  a  hypothesis,  regard  phthalic  acid  as  the 
true  carrier  of  biological  activity  and  suggest  that  natural  vitamin  K 
and  its  synthetic  analogues  be  regarded  as  provitamins.  Recently  these 
authors  have  isolated  phthalic  acid  from  the  urine  of  man  and  of  the  dog 
after  the  administration  of  menadione.  Menadione  itself  was  not  found 
in  the  urine,  whereas  administered  phthalic  acid  was  excreted  quantita- 
tively and  unchanged.  These  finding  have  some  strong  suggestive 
supporting^  evidence.  Dicumarol,  a  vitamin  K  antagonist,  owes  its  activ- 
ity to  dec^radation  to  a  simpler  compound,  namely,  salicylic  acid.  The 
vitamin  K  compounds  may  owe  their  antihemorrhagic  activity  to  their 
easy  dee^radation  to  phthalic  acid.  The  attractive  hypothesis,  which  re- 
sults, is  that  the  antagonism  of  dicumarol  to  vitamin  K  is  due  to  the 
competition  in  vivo  of  two  structurally  similar  molecules.  Phthalic  acid 
possesses  two  carboxyl  groups  on  a  benzene  ring;  salicylic  acid  possesses 
one  carboxyl  and  one  hydroxyl  group.   The  competition  of  structurally 

Vol.  I.  948 


452(30)  VITAMINS  AND  VITAMIN  DEFICIENCY 

similar  molecules,  acting  as  either  substrates  or  co-enzymes  for  enzyme 
systems,  is  common  knowledge  among  chemists. 

In  so  far  as  is  known  at  present,  vitamin  K  has  no  relationship  to 
immunity,  infection,  pregnancy  and  lactation,  the  nervous  system, 
gastro-intestinal  tract  or  cardiovascular  system,  but  it  is  associated  inti- 
mately with  nomial  physiological  function  of  the  liver  and  with  proper 
coagulation  of  the  blood.  Its  exact  role  in  coagulation  of  the  blood  is 
not  known.  It  is  known  to  be  necessary  for  proper  formation  of  pro- 
thrombin, but  the  manner  in  which  this  is  accomplished  remains  to  be  de- 
termined. A  deficiency  of  vitamin  K  arising  from  any  cause  produces  a 
deficiency  of  prothrombin  in  the  circulating  blood,  and  in  all  instances 
except  those,  in  which  there  is  severe  hepatic  damage,  this  deficiency 
of  prothrombin  can  be  corrected  by  the  proper  administration  of 
vitamin  K. 

Sources 

Among  the  richest  sources  of  vitamin  Ki  are  the  green,  leafy  tissues 
of  spinach,  alfalfa,  kale,  cauliflower,  carrot  tops  and  chestnuts.  Tomatoes, 
hemp  seed  and  soy  bean  oil  also  are  good  sources,  but  fruits  and  cereals 
are  poor  sources  of  the  vitamin.  The  parts  of  the  plant,  which  contain 
chlorophyll,  usually  have  the  largest  amounts  of  vitamin  K. 

Vitamin  K2  occurs  in  many  bacteria,  whereas  yeast,  molds  and  fungi 
contain  little  or  no  vitamin  K.  The  vitamin  K  activity  of  feces  of  the 
horse,  cow,  sheep,  hog  and  man  has  been  well  established.  Apparently 
during  the  growth  of  the  bacteria  the  vitamin  K  is  synthesized  and  is 
retained  within  the  bacteria,  since  the  filtrate  of  the  culture  medium, 
which  is  free  of  the  bacteria,  contains  none  of  the  vitamin.  Ether  ex- 
tracts*^ of  these  bacteria,  however,  have  vitamin  K  activity.  Dried 
human  feces,  both  normal  and  acholic,  are  rich  in  the  vitamin,  but  the 
vitamin  K  activity  of  feces  undoubtedly  results  from  the  bacterial  con- 
tent within  them. 

Most  animal  materials  contain  very  little  vitamin  K.  Milk  and  eggs 
contain  small  amounts,  and  hog  liver  is  very  rich  in  this  vitamin. 


Experimental  Pathological  Physiology 

In  the  presence  of  deficiency  of  vitamin  K  the  prothrombin  content 
of  the  blood  is  markedly  decreased,  and  the  blood  clotting  time  may  be 
Vol.  I.  948 


VITAMINS  K:  PATHOLOGICAL  PHYSIOLOGY     452(31) 

considerably  prolonged.    In  animals  the  principal  symptom  to  appear 
during  deficiency  of  vitamin  K  is  the  occurrence  of  hemorrhage. 

In  chicks  fed  on  material  deficient  in  vitamin  K  there  develop  sub- 
cutaneous, intramuscular  and  internal  hemorrhages,  profuse  bleeding 
from  minor  abrasions  and  a  delayed  clotting  time  associated  with  a  low 
content  of  prothrombin  in  the  plasma.  Injuries  in  a  wide  sense  may 
determine  the  occurrence  and  severity  of  these  hemorrhages.  Results 
of  studies  by  many  investigators  of  the  content  of  prothrombin  in  the 
plasma  in  hemorrhagic  chick  disease  show  that  hemorrhages  do  not 
occur  until  the  content  of  prothrombin  has  declined  to  about  10  to  15 
per  cent,  of  normal.  It  has  been  indicated  that  the  clotting  time  is  de- 
layed only  if  the  content  of  prothrombin  has  declined  to  less  than  30 
or  40  per  cent,  of  normal.  Thus,  early  in  the  course  of  the  disease,  when 
•  deficiency  of  the  vitamin  is  less  severe,  the  content  of  prothrombin  in 
the  plasma  may  be  reduced  considerably,  and  yet  the  clotting  time  will 
remain  normal.  This  is  extremely  important  as  a  clinical  factor.  Defi- 
ciency of  prothrombin  also  has  been  produced  in  rats,  mice,  ducklings, 
voung  geese,  pigeons,  canaries  and  rabbits  that  were  subsisting  on  diets 
deficient  in  vitamin  K. 

It  has  been  long  known  that  in  dogs,  which  have  biliary  fistulas,  an 
abnormal  tendency  to  bleed  develops  in  addition  to  many  pathological 
complications.  Furthermore  it  has  been  pointed  out  that  continuous 
subsequent  feeding  of  bile  to  such  animals  will  correct  this  abnormality. 
This  tendency  toward  bleeding  of  dogs,  which  have  biliary  fistulas,  was 
shown  later  to  be  caused  by  deficiency  of  prothrombin  which  could  be 
corrected  by  the  administration  of  vitamin  K.  In  rats,  which  have  renal 
biliary  fistulas,  there  is,  likewise,  a  diminution  in  the  circulating  pro- 
thrombin which  can  be  corrected  by  the  administration  of  vitamin  K. 

Deficiency  of  vitamin  K  can  be  produced  also  by  alteration  of  the 
bacterial  flora  of  the  intestinal  tract.  It  was  observed  first  that  hypo- 
prothrombinemia  developed  in  young  rats  given  sulfaguanidine  in  puri- 
fied diets,  and  that  the  effect  on  the  content  of  prothrombin  in  the  blood 
could  be  counteracted  by  the  administration  of  vitamin  K^^  It  was 
found  that  the  hypoprothrombinemic  effect  of  this  drug  could  be  pre- 
vented by  the  administration  either  of  p-aminobenzoic  acid  or  of  a  liver 
fractional  Sulfapyrazine,  sulfadiazine  or  sulfathiazole,  when  fed  to  rats 
at  a  I  per  cent,  level  in  purified  diets,  results  in  the  regular  production  of 
severe  hypothrombinemia  within  2  to  3  weeks.  Sulfaguanidine,  sulfanil- 
amide and  succinyl  sulfathiazole  are  much  less  effective  in  producing 
Vol.  I.  948 


452(32)  VITAMINS  AND  MTAMIX  i:)FFTaF,XCY 

this  phenomenoif  \  The  action  of  these  drugs  is  thought  to  be  the  result 
of  tlieir  effect  on  coliform  organisms  in  the  intestinal  tract"". 

It  has  been  reported  that  female  rabbits  fed  a  vitamin  K-deficient 
diet  for  40  days  and  mated  with  normal  males  aborted  during  the  late 
first  or  early  second  trimester  of  pregnancy.  Retroplacental  hemor- 
rhages were  considered  responsible  for  the  abortions,  and  although  the 
content  of  prothrombin  was  lowered  in  the  rabbits,  it  did  not  reach  a 
critical  level.  If  the  females  wtre  bred  once  more,  while  they  were  sub- 
sisting on  the  deficient  diet,  abortions  occurred,  but  normal-term  preg- 
nancies resulted  when  vitamin  K  \\'as  added  to  the  diet"^ 


Human  Requirements  of  \^ttamtn  K 

Although  it  has  been  shown  experimentally  that  vitamin  K  is  re- 
quired by  the  chick,  goose,  duck,  canary,  pigeon,  turkey,  rat,  rabbit, 
mouse,  dog  and  man"'\  yet  the  exact  amount  of  vitamin  K  required  by 
these  various  species  is  unknown.  It  is  known,  however,  that  pure  vita- 
min Ki  or  synthetic  compounds,  which  exhibit  vitamin  K  activity  in 
doses  of  I  to  2  mgm.,  are  capable  of  correcting  deficiency  of  vitamin  K 
in  most  instances.  In  diseases,  in  which  there  is  acute  or  chronic  hepatic 
damage  of  a  severe  degree,  even  large  doses  of  vitamin  K  are  ineffective 
in  correcting  the  deficiency  of  prothrombin.  In  deficiency  of  prothrom- 
bin, produced  in  the  human  being  by  the  administration  of  dicumarol 
[3,3'-methylenebis  (4-hydroxycoumarin)  ],  as  much  as  40  mgm.  of  men- 
adione may  be  needed  to  correct  the  hvpoprothrombinemia. 

As  a  rule,  large  doses  of  vitamin  K,  when  administered  to  man,  do 
not  produce  hyperprothrombinemia,  but  the  oral  administration  of  large 
doses  of  menadione  to  the  dog,  rabbit  or  rat  induces  this  condition, 
which  may  persist  for  several  days^". 

The  discussion  of  requirements  of  vitamin  K  for  the  human  infant 
is  reported  under  the  section  entitled  "Deficiency  of  prothrombin  among 
newborn  infants." 

Deficiency  of  Vitamin  K  in  Man 

There  are  a  number  of  conditions  in  which  a  deficiency  of  prothrom- 
bin exists  or  can  be  produced  in  man  that  can  be  corrected  by  the 
administration  of  vitamin  K^"'"*.  Such  a  deficiency  may  occur  in  any  of 
the  following  circumstances. 

Vol..  T.  948 


MTA.MINS  K:   DF.FICIENCV 


45-(33) 


First,  after  ingestion  of  a  diet  inadequate  in  vitamin  K.  This  con- 
dition is  rare,  but  the  clinical  observation  is  well  supported  by  the  experi- 
mental production  of  low  values  for  prothrombin  in  the  blood  of  rabbits 
and  mice  after  they  have  been  caused  to  subsist  on  diets  deficient  in 
vitamin  K. 

Second,  in  the  presence  of  inadequate  intestinal  absorption.  This 
may  result  from  ( i )  lack  of  bile  in  the  intestine  because  of  decreased 
secretion  of  bile  salts,  (2)  obstruction  of  the  bile  duct  from  any  cause, 
or   (3)   inadequate  absorption  attributable  to  various  intestinal  lesions 


mm 


7777m 


'/m/mm 


Normal -- 

SpruG 

Intestinal  poluposis 

(colectomi]) 
Chronic  ulcerative  colitis 

Intestinal   fistula 

Postoperative   gastric     \////////////////////7m 
retention  ^.^^^^^^^^^^^^^.^^^^^^.^^ 

Gastrocolic   fistula 

Intestinal   obstruction    \//////J//////////////////////////m 


'//////////A 


V7777777A 


mm 


'///////////A 


'////////mm 


miA 


a 


as      50      75     100    las 
Quick   prothrombin    time 
(seconds) 

*  Bleeding 


0       50      100 
Quantitative 
prothrombin 
(%  normal) 


Fig.  15.  The  various  intestinal  disturbances  with  ^\•hich  may  be  associated  a  de- 
ficiency of  prothrombin  that  can  be  readily  corrected  by  the  proper  administration 
of  compounds  with  vitamin  K  activity.  (Butt,  H.  R.  and  Snell,  A.  M.:  Vitamin  K, 
VV.  B.  Saunders  Company,  Philadelphia,  1941.) 

such  as  intestinal  obstruction  and  short-circuiting  surgical  procedures. 
It  likewise  has  been  demonstrated  that  severe  diarrheal  diseases,  such  as 
ulcerative  colitis,  sprue  or  celiac  disease,  may  result  in  deficiency  of  pro- 
thrombin^"^ (Fig.  15).  A  deficiency  of  prothrombin  as  a  cause  of  bleed- 
ino-  in  cases  of  various  intestinal  disturbances  is  something  new  in  clinical 
medicine.  Although  instances  of  deficiency  in  prothrombin  referable 
to  the  effect  of  intestinal  disturbances  are  not  often  encountered,  they 
do  comprise  a  rather  distinct  group  and  one  which  warrants  close  obser- 
vation. A\'hen  patients,  who  have  extensive  disease  of  the  intestine  such 
as  sprue,  chronic  ulcerative  colitis,  intestinal  obstruction  or  ileitis,  or  who 
Vol.  L  948 


452(34)  VITAMINS  AND  VITAMIN  DEFICIENCY 

have  undergone  multiple  short-circuiting  operations  on  the  intestinal 
tract  experience  hemorrhage  either  before  or  after  surgical  treatment, 
deficiency  in  prothrombin  should  be  recognized  and  corrected  before 
other  forms  of  treatment  are  instituted.  One  of  the  most  important 
points  in  the  management  of  these  conditions  is  that  the  physician  follow 
the  content  of  prothrombin  in  the  blood  closely  before  and  after  opera- 
tion in  all  cases  of  abnormalities  of  intestinal  mucosa,  particularly  in 
cases  in  which  the  postoperative  condition  requires  continued  aspiration 
of  gas  and  secretions  from  the  intestinal  tract.  This  practice  has  solved 
the  mystery  of  obscure  intestinal  bleeding,  which  occurs  frequently  in 
such  cases,  and  definitely  has  reduced  postoperative  morbidity  and 
fatality. 

Third,  injury  to  the  liver.  There  is,  of  course,  considerable  evidence, 
both  clinical  and  experimental,  to  indicate  that  the  liver  plays  an  active 
part  in  the  formation  of  prothrombin,  and  that  any  severe  injury  to  this 
organ  results  in  a  deficiency  of  prothrombin^"-.  It  has  been  well  demon- 
strated clinically  and  experimentally  that  primary  hepatic  disease  such  as 
cirrhosis,  liver  atrophy  or  chronic  hepatitis  frequently  is  accompanied 
by  deficiency  of  prothrombin.  This  deficiency  of  prothrombin  is  not 
the  result  of  deficiency  of  vitamin  K  but  apparently  is  the  direct  result 
of  severe  hepatic  damage.  Under  these  conditions  the  deficiency  of 
prothrombin  usually  is  not  relieved  by  the  administration  of  vitamin  K 
in  any  amount.  It  is  well  to  recall  that  instances  of  severe  hepatic  damage 
occur  in  any  disease  in  which  the  liver  might  be  involved,  and  although 
this  group  of  cases  is  somewhat  small,  this  possibility  must  be  kept  in 
mind. 

Fourth,  ingestion  of  salicylates.  It  has  been  reported  that  when  sali- 
cylates are  administered  to  man  there  is  a  reduction  of  prothrombin  in 
the  circulating  blood^"^'^''*'^°^  and  that  this  deficiency  of  prothrombin 
can  be  corrected  by  the  administration  of  vitamin  K^"''.  These  facts  now 
have  been  confirmed  amply.  The  effect  of  salicylates,  however,  even  in 
large  doses,  on  the  prothrombin  content  of  the  blood  is  not  great,  and 
the  occurrence  of  hemorrhagic  manifestations  is  unlikely^"^  If  any 
surgical  procedure  is  contemplated  for,  or  arises  as  an  emergency  in,  a 
patient,  who  is  ingesting  large  amounts  of  salicylates,  then  vitamin  K 
obviously  should  be  given  before  and  after  operation. 

Fifth,  ingestion  of  dicumarol.  When  this  compound  is  administered 
to  animals  or  to  man  there  results,  after  action  in  vivo,  a  decrease  in  the 
prothrombin  content  of  the  circulating  blood.  The  mechanism,  through 
which  the  content  of  prothrombin  is  reduced,  still  is  obscure,  but  evi- 

VoL,  I.  948 


VITAMINS  K:  PROTHROMBIN  DEFICIENCY        452(35) 

dence  suggests  that  the  synthesis  of  prothrombin  is  prevented.  This 
occurs  either  through  the  same  mechanism,  which  prevents  vitamin  K 
from  catalyzing  prothrombin  synthesis,  or  through  a  direct  action  on 
the  prothrombin^"*. 

At  the  low  levels  of  menadione,  which  ordinarily  would  correct  a 
nutritional  deficiency  of  vitamin  K,  the  hypoprothrombinemic  action 
of  dicumarol  is  not  prevented.  Large  doses  of  vitamin  K,  however,  will 
correct  the  deficiency  of  prothrombin  produced  by  dicumaroP"'*""'^" 

Deficiency  of  Prothrombin  Among  Newborn  Infants 

It  is  rather  generally  agreed  that  during  the  first  few  days  of  an 
.infant's  life  a  deficiency  of  prothrombin  exists  in  the  circulating  blood. 
Waddell  and  Guerry  and  their  associates  "-  were  the  first  to  report  the 
important  discovery  that  this  physiological  deficiency  of  prothrombin 
of  newborn  infants  and  the  bleeding  tendency,  which  sometimes  devel- 
oped, could  be  corrected  by  the  administration  of  vitamin  K.  Since  that 
time  numerous  reports  have  appeared  concerning  the  effect  of  the  var- 
ious compounds  possessing  vitamin  K  activity  on  the  content  of  pro- 
thrombin of  newborn  infants,  and  the  effect  of  such  compounds  on  the 
hemorrhage  which  occurs  frequently.  The  important  suggestion  also 
has  been  made  that  the  deficiency  of  prothrombin  existing  at  the  time  of 
birth  might  account  in  many  instances  for  the  intracranial  hemorrhages, 
which  sometimes  follow  protracted  labor,  and  which  result  frequently  in 
permanent  paralysis  of  the  infant. 

In  Fig.  16  are  plotted  the  prothrombin  levels  during  the  first  6  days 
of  life  as  reported  from  various  laboratories  which  employed  a  variety  of 
methods  for  the  measurement  of  prothrombin  in  the  blood.  On  the 
basis  of  this  figure  one  would  be  justified  in  concluding  that  the  clinical 
material  studied  in  these  various  cities  was  different,  and  that  each  un- 
doubtedly represents  specialized  classes  of  patients  studied  under  special 
conditions.  Smith  and  Warner^^^  believed  that  the  clue  to  these  discrep- 
ancies lies  in  the  fact  that  the  vitamin  K  intake  of  the  pregnant  woman 
has  much  to  do  with  the  amount  of  the  vitamin  received  by  the  infant 
and  hence  with  the  content  of  prothrombin  of  the  latter.  ^Vaddell  and 
Guerry^"  have  shown  that  the  content  of  prothrombin  in  the  newborn 
infant  is  much  higher  in  summer  than  in  winter.  This  probably  results 
from  the  large  intake  of  green  vegetables  during  the  summer  months. 
The  results  recorded  in  the  summer  are  shown  in  curve  4A  (Fig.  16) 
and  the  results  obtained  in  winter  appear  in  curve  4B. 
Vol.  I.  948 


452(3<^) 


VITAMINS  AND  VITAMIN  DEFICIENCY 


The  exact  cause  of  this  deficiency  of  vitamin  is  not  completely 
known.  It  has  been  suggested  that,  as  soon  as  the  presence  of  bacterial 
flora  of  the  intestinal  tract  is  established,  the  infant  is  capable  of  synthe- 


0  12  3  4 

AG  E  IN  DAYS 
Fig.  1 6.  The  content  of  prothrombin  in  the  blood  of  an  untreated  infant  during  the 
first  six  days  of  hfe.  Curves  i  and  2  were  devised  by  Owen,  Hoffman,  Ziffren  and 
Smith  in  Iowa  City.  Curve  i  is  based  on  the  "bedside  test".  Curve  2  was  devised 
according  to  the  method  of  Quick.  Curve  4A  and  4B  were  prepared  by  Waddell  and 
Guerry  (114)  in  Charlottesville,  Virginia;  they  used  a  microadaptation  of  Quick's 
method  by  Kelly  and  Gray.  Curve  4A  was  charted  during  winter  and  early  spring; 
curve  4B  was  computed  during  late  spring  and  early  summer.  Waddell  and  Guerrv 
expressed  their  results  in  the  form  of  the  prothrombin  time  (in  seconds).  To  facili- 
tate comparison,  these  values  have  been  converted  into  "percentage  of  normal  adult 
values"  with  the  aid  of  the  conversion  curve  of  Quick.  Curve  5  was  prepared  bv 
Owen,  Hoffman,  Ziffren  and  Smith,  in  Iowa  City;  They  employed  the  two-stage 
prothrombin  method  of  Warner,  Brinkhous  and  Smith.  Curve  6  was  computed  b\ 
Kato  and  Poncher  in  Chicago;  they  utilized  a  micromethod  devised  by  Kato.  (Smith, 
H.  P.  and  Warner,  E.  D.:  X^itamin  K,  Clinical  Aspects,  in  The  Biological  action  of 
the  vitamins;  a  symposium,  Edited  by  E.  A.  Evans,  Jr.,  The  University  of  Chicago 
Press,  Chicago,    1942.) 

sizing  vitamin  K,  a  fact  which  has  been  well  proved  experimentally. 
This  explanation,  however,  does  not  explain  the  delay  in  the  return  to 
normal  of  the  value  for  prothrombin,  a  delay  which  occurs  in  many  in- 
fants. To  explain  this  phenomenon  it  must  be  recalled  that  the  liver  of 
Vol.  T.  948 


VITAAilNS  K:  PROTHROMBIN  DEFICIENCY        452(37) 

the  newborn  infnnt  is  iin;iblc  to  secrete  sufficient  bile,  that  the  absorp- 
tion of  fat  is  very  Hniited  and  that  gastrointestinal  hvperniotihty  is  the 
rule.  Thus,  even  though  vitamin  K  is  present,  proper  absorption  of  the 
vitamin  would  be  theoretically  unlikely  until  the  digestive  function  ap- 
proaches nomial.  This  occurs  on  about  the  third  or  fourth  day  of  life. 
To  support  the  suggestion  that  the  presence  of  bacterial  jflora  in  the 
intestinal  tract  is  connected  intimately  with  the  return  of  the  value  for 
prothrombin  to  normal  at  the  end  of  the  third  day,  some  investigators 
have  shown  that  extra  feeding,  started  within  2  hours  after  delivery  of 
the  infant,  can  prevent  the  subsequent  development  of  hvpoprothrom- 
binemia.  Evidence  M^hich  tends  to  refute  these  theories  will  be  discussed 
a  little  further  alonjr. 


120  - 
110  - 


I  V  MAINTENANCE-^ 

„.o O' 

"         OY  -PROPHYLACTIC 


-^o- ^  ,IU  Y  •t-'KUKM 


2  3 

AGE     IN     DAYS 

Fig.  17.  The  response  of  infants  to  variable  doses  of  vitamin  K.  The  compound 
used  as  a  source  of  vitamin  K  activity  was  the  water-sokible  4-amino-2-methvl-i- 
naphthol  (synkamin).  Administration  was  by  intramuscular  injection  (Smith,  H.  P. 
and  Warner,  E.  D.:  Vitamin  K,  Clinical  Aspects,  in  The  biological  action  of  the 
vitamins;  a  symposium,  Edited  by  E.  A.  Evans,  Jr.,  The  Universiay  of  Chicago  Press, 
Chicago,   1942.) 

It  has  been  shown  by  Sells,  Walker  and  Owen^^^  that  the  minimal 
vitamin  K  requirement  of  the  infant  is  extremely  low.  Their  results 
modified  by  Smith  and  Warner^^^  are  shown  in  Fig.  17.  The  uppermost 
curve  in  this  figure  shows  that  i  microgram  of  vitamin  K,  given  daily, 
is  adequate  to  maintain  the  content  of  prothrombin  at  normal.  It  is  also 
shown  in  the  second  curve  that  a  dose  of  10  micrograms  usually  would 
prevent  the  decrease  shown  in  the  untreated  controls.  In  Fig.  17  also 
is  seen  a  curve  which  shows  that,  if  i  microgram  is  given  on  the  third  day 

Vol..  T.  94 S 


452(38)  VITAMINS  AND  VITAMIN  DEFICIENCY 

of  life,  it  is  followed  in  10  hours  by  an  increase  in  the  content  of  pro- 
thrombin from  30  per  cent,  of  normal  to  the  percentage  of  95. 

As  already  mentioned,  nearly  all  investigators  have  noted  that  the 
content  of  prothrombin  increases-  until  it  has  exceeded  the  so-called  dan- 
ger point  as  soon  as  the  infant  receives  an  adequate  amount  of  milk.  It 
always  has  been  assumed  that  milk,  since  it  was  a  poor  source  of  vitamin 
K,  served  merely  to  introduce  bacterial  flora  into  the  intestinal  tract 
and  that  vitamin  K  was  produced  by  these  bacteria.  The  work  of  Sells, 
Walker  and  Owen^^^  has  shown,  however,  that  milk  does  contain  an 
amount  of  prefomied  vitamin  K  adequate  to  meet  the  minimal  require- 
ments of  the  infant. 

To  recapitulate,  it  appears  that,  when  large  amounts  of  vitamin  K 
are  given  to  the  pregnant  female,  the  vitamin  is  transmitted  through  the 
placenta  and  that  some  is  stored  in  the  fetus.  According  to  Smith  and 
\Varner"^  if  the  diet  of  the  mother  has  been  adequate,  the  content  of 
prothrombin  in  the  infant  is  at  a  safe  figure  at  birth.  Frequently  this  is 
not  the  case,  and  because  of  the  infant's  lack  of  food  intake  a  deficiency 
of  vitamin  K  develops  rather  rapidly.  During  the  critical  4  days  that 
follow  birth,  a  single  prophylactic  dose  of  10  micrograms  is  sufficient  to 
maintain  a  normal  content  of  prothrombin.  If  the  mother  is  given  i 
mgm.  of  the  vitamin,  similar  protection  results.  It  seems  that  the  vita- 
mins may  be  distributed  between  mother  and  fetus  almost  in  proportion 
to  body  weight.  Apparently  the  infant  is  competent  to  manufacture 
adequate  amounts  of  prothrombin,  if  vitamin  K  is  present  in  sufficient 
amounts. 

On  the  basis  of  work,  reports  of  which  are  now  available,  it  appears 
that  a  dose  of  from  0.5  to  i  mgm.  of  2-methyl-i,  4-naphthoquinone  or 
of  any  of  the  other  synthetic  quinone  compounds  available  commercially 
is  sufficient,  in  most  instances,  to  control  certain  hemorrhagic  disease 
of  the  newborn  and  that,  if  it  is  administered  at  the  time  of  birth,  it  will 
prevent  transitory  hypoprothrombinemia.  It  must  be  remembered  that 
failures  also  can  occur  in  the  treatment  of  infants,  if  sufficient  hepatic 
damage  has  occurred. 

It  has  been  reported  and  well  established  by  several  groups  of  work- 
ers that  the  administration  of  vitamin  K  to  mothers  prior  to  delivery  wall 
prevent  the  usual  decrease  in  the  content  of  prothrombin  in  the  blood, 
which  is  observed  among  newborn  infants,  and  that  the  administration 
of  vitamin  K  to  the  newborn  infant  also  will  increase  the  concentration 
of  prothrombin  in  the  plasma"'^"''^^*. 

On  the  basis  of  results  of  work  now  available,  it  appears  that  2  mgm. 

Vol.  I.  948 


VITAMINS  K:  METHODS  FOR  MEASURING        452(39) 

of  menadione  given  by  mouth  to  a  mother  a  half  hour  to  forty-eight 
hours  before  dehvery  'is  effective  in  preventing  hemorrhagic  disease  of 
the  newborn  infant"^  There  is  good  evidence  to  indicate  that,  although 
the  feeding  of  vitamin  K  to  the^infant  after  birth  increases  the  concen- 
tration of  prothrombin,  the  concentrations  in  these  instances  are  not  so 
high  as  those  achieved  by  antepartum  administration  of  the  vitamin  to 

the  mother. 

Many  workers  believe  that  instances  of  cerebral  hemorrhage  occur- 
ring in  the  course  of  birth  with  minimal  trauma  are  precipitated  by  small 
hemorrhages  which  endure  for  a  number  of  days.  For  this  reason  many 
workers  interested  in  this  problem  believe  that  the  lives  of  some  of  the 
infants  concerned  might  be  saved,  if  the  blood  at  birth  exhibits  better 
properties  of  coagulation.  Most  investigators  believe  that  some  form  of 
vitamin  K  should  be  administered  to  every  mother  at  the  onset  of  labor. 
Some  still  insist  that  the  vitamin  also  should  be  given  to  the  newborn 
infant  as  an  added  precaution.  In  any  event,  the  plan  is  so  simple,  the 
vitamin  so  cheap  and  the  toxic  reactions  so  minimal  that  this  program 
should  be  adopted  universally  in  the  hope  of  preventing  injury  at  birth"". 

Methods  for  Measuring  Deficiency  of  \^ita.min  K 

Since  no  international  standard  of  unity  has  been  established  for  vita- 
min K,  many  methods  of  assay  and  standards  of  unity  have  arisen "\  The 
wide  interest  displayed  in  vitamin  K  and  associated  naphthoquinones  has 
o-iven  rise  to  the  need  for  convenient  and  accurate  methods  for  their  esti- 
mation. A  step  in  this  direction  was  made  by  Trenner  and  Bacher"',  who 
described  a  method  by  which  many  quinone-like  substances  can  be  as- 
sayed. Others  recently  have  also  reported  work  in  this  direction'''''^''\ 
'  Of  clinical  importance  are  the  methods  by  which  deficiency  of  vita- 
min K  can  be  recognized  by  simple  laboratory  procedures.  Several  excel- 
lent methods  for  the  measurement  of  deficiency  of  prothrombin  in  the 
blood  of  man  have  been  described,  but  in  the  experience  of  many  the 
method  developed  by  Quick  and  his  associates^-^^'"^'"''^'''-^'"'^'''^''  has  been 
found  adaptable  for  general  use  in  the  clinical  laboratory.  The  method 
developed  by  Warner  and  his  associates'''''''"  also  is  used,  with  modifi- 
cation, in  many  laboratories.  Details  of  these  methods  are  given  in  several 
publications'^^''^^''^^''^^''^^''^''^^ 

The  so-called  bedside  method  has  come  into  considerable  use,  and  is 
reported  to  be  of  great  value  for  the  general  practitioner.  Suitably  com- 
pact sets  for  making  this  measurement  at  the  bedside  now  are  available 
Vol.  I.  948 


452(40)  MTA.MTXS  AND  MTA.MIN  DEFICIENCY 

comnicrciallv^''.  Several  niicromethods  for  the  measurement  of  defi- 
ciency of  prothrombin  of  infants  also  have  been  described  and  are  used 
routinely  in  manv  institutions^"^'^^'"''^^"'^^'^''^ 

It  must  be  admitted  that  all  current  methods  for  the  estimation  of 
prothrombin  are,  of  necessity,  indirect.  Ho\\ever,  certain  of  these 
methods  for  tlie  measurement  of  prothrombin  are  the  most  nearly  accu- 
rate methods  available  at  present  for  estimation  of  the  tendency  of  a 
patient  to  bleed  in  the  presence  of  suspected  deficiency  of  prothrombin. 
The  inff)rmation  afforded  by  the  measurement  of  prothrombin  in  the 
circulating  blood  is  much  more  nearly  accurate  in  the  prediction  of  the 
tendency  of  a  patient  to  bleed  than  is  the  measurement  of  the  coagulation 
or  bleeding  time  as  formerly  used  in  the  consideration  of  such  tendencies. 

Toxicity 

To  date  no  serious  unto\\ard  reaction  has  been  observed  among  per- 
sons who  have  received  reasonable  therapeutic  doses  of  natural  concen- 
trates of  vitamin  K,  synthetic  vitamin  Ki  or  any  of  the  synthetic  com- 
pounds exhibiting  antihemorrhagic  activity  now  available  commercially. 
x\n  effect  has  not  been  noted  on  blood  pressure,  respiration,  permeability 
of  capillaries  or  urinary  excretion  after  the  administration  of  any  of  these 
compounds.  It  has  been  observed,  however,  that  doses  of  menadione  as 
large  as  180  mgm.  administered  orally  to  human  beings  result  in  vomiting 
and  porpii\rinuria.  Other  workers  have  noted  that  anemia  followed  the 
administration  of  large  doses  of  vitamin  K^^^  These  huge  doses,  how- 
ever, are  so  obviously  greater  than  those  employed  for  therapeutic  use 
that  at  present  it  appears  safe  to  continue  the  therapeutic  administration 
of  these  synthetic  compounds.  Fieser  wisely  pointed  out  that  some 
clinical  consideration  should  be  given  to  the  possible  conflict  or  other- 
wise undesirable  characteristics  \Afiich  may  be  associated  ^^'ith  conjugates 
resulting  from  administration  of  menadione.  He  pointed  out  that  the 
delayed  action  of  the  administered  material  would  appear  to  be  subject 
to  considerable  uncertainty,  and  that  the  wide  opportunity  for  trans- 
formation of  different  types  would  lead  one  to  expect  a  variability  in  the 
response,  depending^  on  the  manner  of  administration  and  the  condition 
of  the  patient""'^^  "-''^ 

Diagnosis  of  Vitamix  K  Deficiency 

The  bleeding  of  patients,  who  have  jaundice,  occurs  most  frequently 
after  surgical  intervention  which  was  calculated  to  relieve  biliary  ob- 
^'oI,.  T.  Q48 


VITAMINS  K:  DIAGNOSIS  ^r-(v) 

struction.  Hemorrhage  usually  is  noted  between  the  first  and  fourth 
postoperative  days,  but  it  may  appear  as  late  as  the  twelfth  to  eighteenth 
day  after  operation.  xAs  is  \vell  known,  cholemic  bleeding  ordinarily 
begins  as  a  slow  oozing  from  the  operative  incision,  from  the  gums  or 
nose  or  from  the  gastrointestinal  tract.  Often,  however,  the  first  evidence 
of  hemorrhage  is  afforded  bv  the  appearance  of  severe  hematemesis  or 
melena.  Such  bleeding  often  is  controlled  temporarily  by  the  transfusion 
of  whole  blood,  but  all  too  frequently  even  the  repeated  transfusions  of 
blood  fails  to  control  the  hemorrhagic  diathesis.  Bleeding  of  this  type  in 
our  experience  and  in  the  experience  of  many  others  invariably  is  asso- 
ciated with  prolongation  of  the  prothrombin  clotting  time. 

Bleeding  of  patients  suffering  from  jaundice  occurs  most  often  in  the 
presence  of  those  conditions  in  which  bile  is  excluded  completely  from 
the  gastrointestinal  tract  such  as  complete  biliary  obstruction  produced 
by  neoplasms  of  the  pancreas,  ampulla  and  gallbladder.  Postoperative 
stricture  of  the  common  bile  duct  is  accompanied  perhaps  by  the  second 
highest  incidence  of  bleeding;  intermittent  obstruction  caused  bv  the 
presence  of  stones  comes  third.  Complete  external  fistulas  are  relatively 
rare  but  often  are  associated  with  bleeding.  Although  bleeding  is  more 
likely  to  occur  in  those  cases  in  which  bile  is  excluded  completely  from 
the  intestine,  yet  the  physician  must  nf)t  overlook  the  fact  that  bleeding 
also  can  occur  in  the  absence  of  jaundice,  if  the  liver  has  been  injured 
considerably  as  the  result  of  chronic  cholecystic  disease.  Although  the 
foregoing  facts  are  somewhat  useful  for  prediction  of  whether  or  not  a 
patient  will  bleed,  the  exceptions  are  so  frequent  that  rigid  clinical  rules 
cannot  be  devised. 

It  has  been  well  demonstrated  experimentally  that,  if  the  hepatic 
parenchyma  is  injured,  the  amount  of  prothrombin  in  the  circulating 
blood  decreases.  It  has  been  demonstrated  further  by  Warner  and  his 
associates  and  by  Bollman  and  his  associates  that,  if  the  hepatic  damage  in 
these  animals  is  too  severe,  the  content  of  prothrombin  in  the  circulating 
blood  does  not  increase  after  the  administration  of  vitamin  K.  Likewise 
it  has  been  well  demonstrated  clinically  that  patients,  who  have  severe 
hepatic  damage,  have  a  decrease  in  the  prothrombin  in  the  circulating 
blood,  and  that  occassionally  they  will  not  respond  to  the  administra- 
tion of  vitamin  K. 

These  instances  of  severe  hepatic  damage  can  occur  in  any  disease  in 
which  the  liver  might  be  involved,  but  most  frequently  they  are  seen  in 
cases  of  cirrhosis  of  the  liver,  in  those  in  which  obstruction  or  stricture 
of  the  common  duct  has  existed  over  long  periods  and  in  those  in  which 

Vo}..  T.  948 


452(42)  VITAMINS  AND  VITAMIN  DEFICIENCY 

there  is  acute  or  subacute  atrophy  of  the  liver  resulting  from  some 
primary  disease  or  associated  with  acute  cholecystitis.  Although  this 
group  of  cases  is  somewhat  small,  it  is  well  to  remember  that  it  does  exist. 
It  is  true  that  repeated  doses  of  vitamin  K  frequently  are  necessary  to 
produce  the  desired  effect,  but  when  the  physician  has  doubled  or  tripled 
the  usual  therapeutic  dose  of  vitamin  K  without  producing  desired 
eifects,  he  can  be  fairly  certain  that,  regardless  of  the  amounts  of  vitamin 
K  administered,  there  will  be  little  increase  of  the  prothrombin  in  the 
circulating  blood. 

A  deficiency  of  prothrombin  as  the  cause  of  bleeding  in  patients  who 
have  various  intestinal  disturbances  is  something  new  in  clinical  medi- 
cine, and  although  instances  of  deficiency  of  prothrombin  referable  to 
the  effects  of  intestinal  absorption  are  not  encountered  often,  yet  they 
do  comprise  a  rather  distinct  group  and  one  which  warrants  further 
investigation.  The  pathological  physiology  concerned  in  such  cases  has 
been  described  herein  under  the  section  on  experimental  pathological 
physiology. 

The  entire  subject  of  bleeding  in  the  newborn  infant  has  been  dis- 
cussed previously  in  this  chapter. 

Obviously  knowledge  of  the  conditions  in  which  deficiency  of  pro- 
thrombin may  occur  is  a  fundamental  requisite  for  the  correct  diagnosis 
of  possible  deficiency  of  vitamin  K.  Although  the  possibility  of  hemor- 
rhagic diathesis  may  be  suspected  in  a  particular  case,  measurement  of 
the  prothrombin  content  of  the  circulating  blood  is  necessary  for  accu- 
rate diagnosis  as  well  as  for  evaluation  of  proper  treatment.  It  must  be 
admitted  that  present  methods  for  measurement  of  the  content  of  pro- 
thrombin in  the  circulating  blood  of  patients  are  subject  to  considerable 
error.  The  decrease  in  the  concentration  of  prothrombin  in  the  circu- 
lating blood  of  man  seems  to  depend  on  certain  unkno\\'n  individual 
factors.  Although  in  certain  instances  the  concentration  of  prothrombin 
in  the  blood  apparently  depends  on  the  degree  of  hepatic  injury,  it  cer-; 
tainly  does  not  have  any  constant  relationship  to  the  type  of  hepatic  or 
biliary  disease  present. 

On  the  basis  of  results  of  the  various  studies  of  Smith  and  his  asso- 
ciates^"-^-^'^"^  it  would  appear  that  bleeding  among  animals  in  the  experi- 
mental laboratory  occurs  when  the  value  for  prothrombin  becomes  less 
than  20  or  25  per  cent,  of  normal,  and  that,  conversely,  so  long  as  the 
value  remains  at  about  20  or  25  per  cent,  bleeding  does  not  occur.  If  this 
conception  is  understood,  it  is  easy  to  see  why,  in  certain  cases,  bleeding 
in  man  may  occur  postoperatively  with  little  warning.   Loss  of  blood, 

Vol.  I.  948 


VITAMINS  K:  TREATMENT  452(4?^ 

surgical  trauma  and  the  effects  of  anesthesia  and  trauma  to  the  hver  ma\' 
reduce  an  already  depleted  supply  of  prothrombin  to  a  dangerously  low 
level;  of  these  factors  mechanical  trauma  is  thought  to  be  the  most  impor- 
tant. The  prothrombin  clotting  time  may,  and  frequently  does,  increase 
with  no  apparent  reason  within  6  to  8  hours,  and  with  this  increase  free 
bleeding  may  occur  without  warning,  and  apparently  normal,  coag- 
ulable  blood  may  become  virtually  incoagulable. 

The  prothrombin  clotting  time  of  the  blood  of  patients,  who  have 
jaundice,  usually  increases  to  some  extent  for  the  first  3  or  4  days  after 
surgical  operation,  but  it  may  increase  rapidly  even  as  late  as  the 
eighteenth  postoperative  day.  For  this  reason  the  prothrombin  clotting 
time  should  be  determined  daily  for  the  first  4  days  after  operation,  and 
then  every  other  day  for  at  least  8  or  10  days  longer.  Any  increase  in 
the  prothrombin  clotting  time  should  constitute  an  indication  for  the 
immediate  oral  or  intravenous  administration  of  vitamin  K.  To  those 
patients  with  a  high  prothrombin  clotting  time  before  surgical  treatment 
it  is  perhaps  wise  to  administer  the  vitamin  daily  for  several  days  after 
surgical  operation,  regardless  of  the  prothrombin  clotting  time.  A  pa- 
tient, whose  blood  has  a  prothrombin  clotting  time  of  more  than  30 
seconds,  should  be  prepared  with  particular  care,  and  one  whose  blood 
has  a  prothrombin  clotting  time  of  more  than  45  seconds  must  be  con- 
sidered to  be  a  potential  bleeder  and  treated  as  such. 

The  same  important  diagnostic  points  also  are  applicable  in  those 
cases  of  various  intestinal  lesions  in  which  a  deficiency  of  prothrombin 
in  the  circulating  blood  may  develop. 

It  is  equally  important  to  follow,  if  possible,  the  prothrombin  clotting 
time  of  newborn  infants,  although  it  is  well  known  that  during  the  first 
few  days  there  is  a  physiological  deficiency  of  prothrombin.  This  cau- 
tion is  particularly  important  if  any  surgical  procedure  is  contemplated 
during  this  period  of  life. 

Unfortunately  the  measurement  of  prothrombin  in  the  circulating 
blood  does  not  always  give  the  exact  index  of  the  tendency  of  the  patient 
to  bleed.  Like  any  laboratory  method  this  method  may  not  give  the 
clinical  information  which  is  always  desirable.  For  these  reasons  prophy- 
lactic treatment  is  much  better  than  treatment  after  bleeding  once  occurs. 

Treatment  of  Vitamin  K  Deficiency 

No  specific  remedy  for  the  prevention  and  control  of  all  instances 
of  bleeding  resulting  from  deficiency  of  prothrombin  has  yet  been  dis- 
VoL.  I.  948 


45^(44) 


VITAMINS  AND  VITAMIN  DEFICIENCY 


covered.  The  proper  administration  of  vitamin  K  or  related  compounds 
in  most  instances  will  be  effective,  but  in  addition  to  obtain  the  best 
results  all  procedures  which  are  known  to  be  of  value  in  the  maintenance 
of  adequate  hepatic  function  must  be  employed.  Obviously  the  first 
objective  in  treatment  of  the  jaundiced  patient,  who  has  a  tendency  to 
bleed,  is  to  restore  continuity  of  the  biliary  passages  and  protection  of 
the  hepatic  parenchyma. 

Regardless  of  the  etiological  factors  involved  in  the  deficiency  of 
prothrombin  in  man,  treatment  in  most  instances  is  essentially  the  same. 
Since  there  are  now  available  \vater-soluble  svnthetic  compounds  with 


g       60 
'^       70 

\ 

1       60 

A 

^•^50 

\ 

•^S"" 

ih" 

v__ 

*       20 

'=  1  mp.  4-aTn!no-S.-Tnethyl    naphthol 

3     10 

■"                                    hydrochloride 

7     6     9     10    u     la 


•"f!^ 

v 


-ophu   of  hvcr 


..^Extemaj    biliary  fistula 


"■a  mf   a-mBi'iHl-l, 
4-naphthocu 


Time    in    hours 

Fig.  1 8  Fig.  19 

Fig.  18.  The  effect  of  the  intravenous  injection  of  1  nigni.  of  4-aniino-2-methyl-i- 
naphthol  livdrochloride  on  the  elevated  prothrombin  clotting  time  of  a  patient  who 
had  obstructive  jaundice.  (Butt,  H.  R.  and  Snell,  A.  M.:  Vitamin  K,  \Y.  B.  Saunders 
Company,    Philadelphia,    1941.) 

Fig.  19.  The  elTect  and  rapidity  of  action  of  the  intravenous  injection  of  2  mgm. 
of  2-methyl-i,4-naphthoquinonc  in  a  case  of  external  biliary  fistula  and  in  one  of 
calculus  of  the  common  bile  duct.  The  fitjure  also  shows  the  failure  of  this  compound 
to  reduce  the  elevated  prothrombin  clotting  time  in  a  case  of  chronic  atrophy  of  the 
liver.  (Butt,  H.  R.  and  Snell,  A.  ]\I.:  Vitamin  K,  W\  B.  Saunders  Company.  Philadel- 
phia, 1941.) 

vitamin  K  activity,  the  procedure  of  giving  bile  salts  to  insure  proper 
absorption  has  been  nearly  discarded.  These  M^ater-soluble  synthetic 
compounds  should  be  administered  orally  or  intravenously  in  doses  of 
from  I  to  2  mgm.  daily  for  several  days  prior  to,  and  after,  surgical  pro- 
cedures in  which  deficiency  of  prothrombin  is  present  or  may  be  ex- 
pected to  develop.  The  rapidity  of  action  of  these  water-soluble  com- 
pounds with  vitamin  K  activity  is  shown  in  Figs.  18  and  iq144. 145.146,147^ 

Most  investisjators  interested  in  this  subject  suggest  that  prior  to 
operation  in  any  of  these  conditions,  regardless  of  the  concentration  of 
prothrombin  in  the  patient's  blood,  vitamin  K  in  some  form  should  be 
administered  for  from  i  to  2  days.  After  operation  the  concentration  of 
prothrombin  in  the  blood  should  be  followed  carefully,  and  vitamin  K 
administered  as  necessars^  In  instances,  in  ^^'hich  the  level  of  prothrom- 

Voi..  I.  948 


VITAMINS  K:  TREATMENT 


452(45) 


bin  in  the  circulating  blood  is  sharply  decreased  before  operation,  vitamin 
K  should  be  adniimstered  routinely  preoperatively  and  postoperatively 
for  several  days,  and  the  concentration  of  prothrombin  in  the  blood 
should  be  determined  for  at  least  8  to  10  days  thereafter. 

Some  workers"'"^  recently  have  felt  that  the  change  effected  in  a 
particular  level  of  prothrombin  by  the  administration  of  vitamin  K  may 
provide  some  index  as  to  the  nature  of  the  disease  being  treated,  with 
particular  reference  to  intrahepatic  and  extrahepatic  jaundice.  Data  now 
at  hand  do  not  unequivocally  establish  this  fact. 


-i™? 


'"I  Is 


"I  5  s  ^'1 

^  e  <3  s>@  c 


^1 


S''! 


Each  arrow  =  1  mO. 
2  muthijl  1-4 
naphthoquinone 


V. 


10     1Z  .  14      16      16     20     ZZ     a4 

Days 


Fig.  20.  The  prothrombin  clotting  time  of  a  patient,  who  had  severe  cirrhosis  of 
the  liver,  and  who  received  over  a  long  period  various  synthetic  preparations  pos- 
sessing marked  antihcmorrhagic  activity.  In  spite  of  these  materials,  the  prothrombin 
clotting  time  remained  elevated.  This  type  of  case  constitutes  a  failure  of  vitamin  K 
to  correct  an  elevated  prothrombin  clotting  time.  (Butt,  H.  R.  and  bnell,  A.  1\1.: 
Vitamin  K,  W.  B.  Saunders  Company,  Philadelphia,   1941.) 

In  some  patients,  who  have  severe  acute  or  chronic  hepatic  damage, 
hemorrhage  develops  from  deficiency  of  prothrombin,  which  cannot  be 
corrected^by  the  administration  of  even  large  amounts  of  blood  or  vita- 
min K  (Fig.  20).  Recently'^'  it  was  reported  that  this  usually  uncon- 
trollable hemorrhajric  diathesis  could  be  corrected  by  the  giving  of  blood 
from  a  donor,  who^24  hours  previously  had  received  a  large  dose  of  vita- 
min K.  Results  of  our  own  work  at  the  Mayo  Clinic  do  not  support  this 

contention^^". 

The  discovery  and  isolation  of  dicumarol  by  Link^^'  and  its  clinical 
application  to  the  prevention  of  thrombosis'''  have  been  important  steps 
in  clinical  medicine.  As  stated  previously,  the  administration  ()f  dicu- 
marol to  human  beings  results  in  a  decrease  in  the  prothrombin  of  the 
blood.  It  is  now  known  by  means  of  the  work  of  several  investiga- 
Vo\..  1.  948 


452(46) 


VITAMINS  AND  VITAMIN  DEFICIENCY 


j.Q^gi  10. 153,154  j-j^^j.  i,^j.gg  doses  of  vitamin  K  will  prevent  this  decrease  in  the 
content  of  protlironibin  in  the  blood  that  follows  the  administration  of 
diciimarol.  Dicumarol  usually  is  administered  to  patients,  who  have 
pulmonary  embolism  or  thrombophlebitis,  or  who  before  surgery  give 
a  history  of  these  difficulties.  The  doses  employed  vary,  but  as  a  rule  a 
single  dose  of  300  mgm.  of  dicumarol  is  administered  on  the  first  day  of 
treatment  and  200  mgm.  is  given  on  the  second  day,  followed  by  the 
administration  of  200  mgm.  each  day,  if  the  prothrombin  time  is  less  than 
35  seconds  (Quick's  method  of  estimation  of  the  prothrombin  content). 
It  was  observed  in  one  series  of  340  patients  that  27  per  cent,  were  "sensi- 

Prothrombin    time  in    seconds    (/ivera^e  norma!  is) 


Fig.  21.  Striking  decrease  in  the  prothrombin  time  after  the  adminstration  of  a 
single  dose  of  menadione  bisulfite  to  eight  patients  who  had  excessive  livpoprothrombi- 
nemia  induced  by  dicumarol.  This  was  the  usual  response  of  the  condition  of  such 
patients.  (Cromer,  H.  E.,  Jr.  and  Barker,  N.  W.:  Proceed.  Staff  Meet.,  Mayo  Clin., 
1944,  XIX,   217.) 

tive"  to  dicumaro^^",  "sensitive"  meaning  that  after  i  or  2  doses  of 
dicumarol  the  prothrombin  time  increased  to  60  seconds  or  more  instead 
of  the  usual  response  of  35  to  55  seconds.  It  was  considered  that  among 
these  27  per  cent,  bleeding  might  occur,  and  for  this  reason  a  simple  and 
effective  method  of  rapidly  lowering  the  prothrombin  time  to  the  neigh- 
borhood of  45  seconds  or  less  was  needed. 

The  striking  effect  on  the  prothrombin  time  exerted  by  the  adminis- 
tration of  large  doses  of  vitamin  K  is  well  shown  in  Fig.  2 1 .  In  these 
cases  a  dose  of  64  mgm.  of  menadione  bisulfite  was  administered  intra- 
venously. This  dosage  is  equivalent  to  40  mgm.  of  2-methyl-i,4-naph- 
thoquinone.  In  an  occasional  case  there  is  no  response  to  these  large 
doses  of  vitamin  K.  Usually,  however,  there  is  definite  lowering  of  the 
prothrombin  time  limit  within  2  hours  after  vitamin  K  has  been  admin- 
istered, and  the  maximal  decrease  in  the  prothrombin  time  is  reached  in 
about  18  hours.  Clinically  these  excellent  responses  to  vitamin  K  indicate 
that  another  valuable  safety  factor  has  been  added  to  dicumarol  therapy. 

Vol.  I.  948 


VITAMIN  C:  CHEMISTRY  452(47) 

VITAMIN  C 

History 

In  1928,  during  studies  on  tissue  respiration  systems,  Szent-Gyorgyi^^^ 
secured  from  adrenal  glands  a  preparation  which  he  subsequently  called 
hexuronic  acid.  This  substance  was  not  tested  for  antiscorbutic  activity, 
however,  at  that  time.  In  1932  W'augh  and  King^^^  succeeded  in  the 
isolation  and  identification  of  vitamin  C,  and  subsequently  it  was  estab- 
lished that  their  product  was  identical  with  the  hexuronic  acid  obtained 
by  Szent-Gyorgyi.  One  year  later  Reichstein,  Grussner  and  Oppen- 
hauer^'^  synthesized  vitamin  C,  which  was  named  ascorbic  acid. 

Chemistry  and  Physiology 

Ascorbic  acid,  having  the  formula  Cr,Hs0.i,  falls  into  the  series  of 
iicxuronic  acid  lactones  and  is  closeh'  related  to  the  sugars.    It  is  an 


I  I 

MO C  H  MO C- 

I  I 

CH.OH  Ct 


l-GULOSE  VITAMIN    C 

(I  -  ASCORBIC    ACID) 


Fig.  22.     Structural  formula  of  i -glucose  and  vitamin  C. 

enediol-lactone  of  an  acid  similar  in  configuration  to  i-gulose.  The 
formulae  for  both  i-gulose  and  ascorbic  acid  are  shown  in  Fig.  22. 

xVscorbic  acid  is  a  crystalline,  colorless  compound  which  is  freely 
soluble  in  water  and  which  has  a  melting  point  of  192°  C.  The  crystals 
may  form  pseudo-orthorhombic  or  monoclinic  patterns  but  tend  to  f omi 
rather  dense  radiation  clusters  (Fig.  23). 

The  crystals  as  such  are  very  stable,  but  in  aqueous  solution  rapid  ox- 
dation  occurs.  The  oxidation-reduction  reaction  of  ascorbic  acid  has  been 
the  subject  of  much  research  since  1933  because  of  the  practical  impor- 
tance of  possible  loss  of  the  vitamin.  It  is  now  known  that  many  organic 
compounds,  including  indophenol  notably,  as  well  as  inorganic  me'tallic 
radicals  such  as  Fe+"  +  +  and  Cu+  +  +,  will  oxidize  ascorbic  acid.  Aero- 

VOL.  I.  948 


4.^^(48) 


VITAMINS  AND  MJAiMIN  DEFICIENCY 


bic  aqueous  oxidation  of  ascorbic  acid  is  accelerated  by  ordinary  as  well 
as  ultraviolet  li^ht,  and  in  the  presence  of  a  flavin  this  reaction  is  en- 
hanced still  more.  The  immediate  product  of  ascorbic  acid  oxidation  is 
dehydroascorbic  acid.  This  product  is  equally  as  potent  as  ascorbic  acid 


ASCORBIC  ACID 


Fig.  23.    Crystalline  ascorbic  acid. 

in  the  treatment  of  scurvy.  While  at  this  level  the  oxidation-reduction 
reaction  is  reversible,  and  it  is  possible  to  reduce  dehydroascorbic  acid  to 
ascorbic  acid  by  hydrogen  sulfide,  cysteine  and  glutathione.  The  rela- 
tionship between  ascorbic  acid  and  dehydroascorbic  acid  is  clearly 
shown  in  Figure  24. 

o=c 1  o=gae  ■  I 

I  aH  I 

0  =  C  .  MO C 

0^=C  HO O  I 

H C >  H C  I 


MO C H 

I 
CH.OH 


•ASCORBIC    ACIO 

CVITAMIN    CJ 


DEHYDROASCORBIC    ACiO 

Fig.  24.    Structural    lOiniula    of    dehydroascorbic    acid    and    i-ascorbic  acid. 


Dehydroascorbic  acid  is  fairly  stable  in  acidic  solutions  of  pH4,  but 
in  solutions  of  a  higher  pH  oxidation  continues  to  an  irreversible  level  in 
which  there  is  structural  rearrangement  with  the  formation  of  a  potent 
reducing  substance.  This  substance,  when  oxidized,  gives  rise  to  oxalic 
acid  and  i-threonic  acid,  and  ascorbic  acid  thus  is  destroyed. 

Both  the  dextro-  and  levo-rotatory  forms  of  ascorbic  acid  lend  them- 

VOL.  I.  948 


VITAMIN  C:  CHEMISTRY  45^^49) 

selves  to  synthesis,  but  it  is  to  he  remembered  that  only  the  levo-rotatory 
form  has  antiscorbutic  properties.  1  he  dextro-rotatory  form  does  not 
protect  against  scurvy.  Several  other  synthetic  substances  have  been 
shown  to  have  antiscorbutic  activity  but  to  a  much  lesser  decree  than 
I -ascorbic  acid. 

The  important  observations  of  Hoist  and  Frolich^ '"^  on  guinea  pigs 
and  pigeons  gave  the  first  hint  that  the  former  animal  required  an  extrin- 
sic supply  of  vitamin  C,  whereas  the  latter  did  not.  This  thought  was 
followed  up,  and  it  is  now  understood  that  of  all  the  animals,  only  the 
primates  and  the  guinea  pig  are  incapable  of  synthesizing  vitamin  C. 
Although  man  is  incapable  of  such  synthesis,  he  is  capable  of  storing  the 
supplied  vitamin.  That  this  is  true  has  been  shown  by  many  well  con- 
trolled experiments,  and  this  fact  explains  the  latent  period  of  three  to 
six  months  or  more  in  the  development  of  scurvy  on  a  vitamin  C  defi- 
cient diet.  Ascorbic  acid  is  widely  distributed  in  body  tissues  and  fluids. 
In  general,  it  can  be  said  that  the  younger  the  tissue  and  the  hiorher  its 
metabolic  activity,  the  greater  will  be  its  ascorbic  acid  content.  This  has 
been  well  shown  by  the  tissue  titration  studies  of  Glick  and  Biskind^^^ 
on  normal  tissue  and  similar  studies  by  Musulin  and  his  associates'*^"  on 
rapidly  growing  tumor  tissue.  All  of  the  glandular  tissues  of  the  body 
contain  significant  amounts  of  ascorbic  acid,  while  the  non-glandular 
body  tissues  and  fluids  contain  a  lesser  amount.  The  followino-  order 
approximates  the  decreasing  concentration  of  ascorbic  acid  in  the  various 
body  tissues  and  fluids;  pituitary  body,  corpus  luteum,  adrenal  cortex, 
young  thymus,  liver,  brain,  testes,  ovaries,  spleen,  thyroid,  pancreas, 
salivary  glands,  lung,  kidney,  intestinal  wall,  heart,  muscle,  spinal  fluid 
and  blood.  The  pituitary  body  contains  260  mgm.  per  100  c.c,  the 
adrenal  gland  200  mgm.  per  100  c.c,  muscle  2  mgm.  per  100  c.c.  and 
blood  plasma  1.2  mgm.  per  100  c.c. 

Certain  of  the  glandular  secretions  and  excretory  products  of  the 
body  also  contain  ascorbic  acid.  Human  milk  contains  four  to  five  times 
the  amount  of  vitamin  C  as  does  cow's  milk.  Thus  nature  has  provided 
for  the  relatively  high  vitamin  C  requirements  of  the  nursing  infant,  who 
requires  about  25  to  30  mgm.  of  ascorbic  acid  a  day,  by  establish- 
ing the  vitamin  C  content  of  human  milk  at  4  to  8  mffm.  per  100  c.c. 
The  young  calf,  on  the  other  hand,  is  independent  of  its  mother  as  far 
as  ascorbic  acid  is  concerned  because  this  animal  can  synthesize  the  vita- 
min. Vitamin  C  is  found  normally  also  in  the  urine,  feces  and  sweat.  By 
far  the  greatest  amount  is  excreted  in  the  urine,  the  total  amount  excreted 
a  day  being  13  to  40  mgm.    Vitamin  C  is  a  so-called  "threshold"  sub- 

VoL.  I.  948 


452(50)  VITAMINS  AND  VITAMIN  DEFICIENCY 

stance  with  a  critical  level  of  excretion  at  approximately  1.4  mgm.  per 
100  c.c.  of  plasma.  The  urinary  excretion  of  the  vitamin  is  enhanced  by 
many  drugs  such  as  ammonium  chloride,  atropine,  sodium  bicarbonate, 
the  salicylates  and  the  barbityrates,  while  insulin  results  in  a  lowered 
excretion.  An  additional  6  to  10  mgm.  is  excreted  in  the  feces,  and  an- 
other 0.55  to  0.64  mgm.  per  100  c.c.  is  excreted  in  the  sweat.  These 
excretion  levels  obviously  depend  upon  dietary  intake  and  increased 
destruction  or  demand  for  the  vitamin. 

The  body  physiological  economy  of  vitamin  C  is  reflected  in  the 
concentration  of  the  vitamin  in  these  various  excretions,  fluids  and  tissues. 
Should  the  extrinsic  supply  of  ascorbic  acid  be  restricted,  there  is  ob- 
served a  disappearance  of  vitamin  C  from  these  elements  in  an  order 
inversely  proportional  to  their  ascorbic  acid  content  in  the  physiological 
state.  Thus,  urinary  excretion  of  vitamin  C  ceases  long  before  the  plasma 
level  is  significantly  reduced.  In  the  same  manner  the  plasma  level  may 
be  zero,  while  the  white  cell-platelet  layer  is  normal.  This  retrograde 
depletion,  so  to  speak,  continues  until  finally  the  pituitary  body  is  de- 
pleted of  the  vitamin.  The  converse  is  true  when  a  primate  or  guinea  pig 
so  depleted  of  vitamin  C  then  is  saturated  with  it.  The  tissues  first  take 
their  share,  then  the  body  fluids,  and  lastly  ascorbic  acid  appears  in  the 
body  excretions.  The  amount  of  the  vitamin  required  to  induce  satura- 
tion thus  is  a  very  rough  estimate  of  the  state  of  vitamin  C  nutrition. 
Crandon  and  Lund^*^^  and  more  recently  Pijoan  and  Lozner^'^^  have  con- 
ducted experimental  studies  in  human  scurvy  which  bear  out  this  concept. 
One  of  the  latter  authors  showed  that  even  though  the  urinary  excretion 
of  vitamin  C  had  long  since  ceased,  and  the  plasma  level  was  0.0  to  0.2 
mgm.  for  twenty  months,  the  white  cell-platelet  layer  contained  25 
mgm.  per  100  c.c,  and  clinical  scurvy  did  not  develop.  These  studies 
have  been  confirmed  by  many  investigators,  and  there  is  little  doubt  but 
that  the  vitamin  C  concentration  in  the  white  cell-platelet  layer  of  cen- 
trifuged  blood  correlates  much  better  with  the  clinical  findings  than  does 
the  vitamin  C  concentration  elsewhere.  It  should  be  remembered,  how- 
ever, that  in  the  normal  physiological  state  there  is  an  excretion  of  vita- 
min C  in  the  urine  and  that  there  is  a  concentration  of  ascorbic  acid  in 
the  blood  plasma  of  1.2  mg.  per  100  c.c.  A  deviation  from  these  findings 
is  not  physiological  and  should  prompt  the  physician  to  suspect  a  defi- 
ciency of  vitamin  C  and  guide  him  to  an  investigation  of  the  dietary  and 
the  application  of  the  vitamin  C  saturation  test. 

The  physiological  functions  of  vitamin  C  include  a  long  list.  How- 
ever, the  most  clearly  defined  of  these  is  the  formation  of  reticulum  and 

Vol.  I.  948 


VITAMIN  C:  PATHOLOGICAL  PHYSIOLOGY       452 (5 1 ) 

collagen  so  as  to  maintain  the  integrity  of  the  intercellular  substance^*^*. 
It  is  believed  that  vitamin  C  may  be  the  sole  factor  which  is  responsible 
for  the  cementing  together  of  the  reticulum  by  a  translucent  matrix  to 
form  collagen  in  between  the  cells  of  tissue.  Vitamin  C  exerts  its  efforts 
only  on  tissue  of  mesenchymal  origin.  The  precise  mechanism  of  this 
function  is  unknown. 

Vitamin  C  is  concerned  further  with  the  over-all  growth  of  the 
organism.  It  has  been  shown  to  be  a  powerful  growth  stimulant  in  the 
young  plant  embryos,  and  it  is  reasonable  to  assume  that  it  has  such  a 
function  in  man.  Growth  and  development  studies  are  such  long-term 
problems  that  only  a  few  such  observations  have  been  made  under  con- 
trolled conditions  in  man  and  in  the  experimental  animal. 

As  to  the  function  of  vitamin  C  as  a  hematopoietic  substance  there  is 
considerable  doubt.  It  has  not  been  shown  conclusively  that  deficiency 
of  ascorbic  acid  itself  is  a  direct  cause  of  the  anemia  seen  in  association 
with  scurvy.  It  is  quite  possible  that  many  other  factors  are  at  work  as 
discussed  in  the  section  on  Pathological  Physiology. 

Accumulating  evidence  is  appearing  that  vitamin  C  may  play  a  role 
in  resistance  to  infection  and  certain  toxins.  King  and  Menten^"  and 
Sigal  and  King^*^^  found  that  guinea  pigs  in  the  "pre-scorbutic"  state  were 
more  sensitive  to  tissue  injury  by  diphtheria  toxin  than  were  normal  ones 
and  that  the  metabolism  of  these  animals  was  lowered  significantly.  The 
latter  is  probably  a  natural  defense  mechanism  to  conserve  the  vitamin  C 
stores.  The  authors  have  observed  that  resistance  to  disease  is  lowered 
significantly  in  general  nutritive  failure,  but  how  much  vitamin  C  is 
directly  responsible  for  this  is  not  known.  The  function  of  vitamin  C 
in  certain  enzyme  systems  still  is  without  proof  or  even  general  agree- 
ment. That  such  a  function  may  exist  is  not  too  unlikely,  but  this  subject 
is  so  imperfectly  understood  that  at  present  no  concrete  statements  can 
be  made. 

It  is  evident  that  there  is  little  precise  knowledge  concerning  the 
physiology  and  metabolism  of  vitamin  C.  Studies  in  vitro  show  poor 
correlation  with  observations  in  vivo.  A  long,  wide  vista  may  lie  before 
science  with  the  recent  advent  of  the  capability  of  marking  carbon  atoms. 
By  this  means  it  may  be  possible  to  follow  ascorbic  acid  through  the  body 
as  it  performs  its  functions  in  vivo. 

Pathological  Physiology 

Deficiency  in  vitamin  C  expresses  itself  most  characteristically  in  the 
development  of  scurvy.   The  pathological  ohysiology  of  vitamin  C  can 
Vol.  I.  948 


452(50  VITAlMINS  AND  VITAMIN  DEFICIENCY 

be  understood  best  from  a  discussion  of  the  pathological  physiology  of 
scurvy,  A  clearer  understanding  of  the  pathological  physiology  of 
scurvy  is  gained,  if  one  recalls  that  the  primary  and  most  clearly  defined 
function  of  vitamin  C  is  the  maintenance  of  the  integrity  of  the  inter- 
cellular substance.  A  lack  or  a  deficiency  of  vitamin  C  results  in  an 
impaimient  of  this  function  with  a  subsequent  manifestation  of  the  symp- 
toms and  signs  of  the  state  we  recognize  as  scurvy.  A  deficiency  of 
vitamin  C  may  result  from  one  or  a  combination  of  any  of  the  several 
follo\\ing  factors;  (i)  a  deficient  dietary  intake,  (2)  impaired  intestinal 
absorption,  (3)  increased  body  requirements  for  the  vitamin,  (4)  faulty 
assimilation,  (5)  faulty  utilization  and  (6)  increased  destruction  in  vivo 
of  the  vitamin. 

A  new  era  in  the  pathogenesis  of  scurvy  was  inaugurated  by  S.  B, 
Wolbach  and  his  associates^'^^-^''*''^'''  from  1926  to  1937,  when  they  showed 
that  the  intercellular  substance  was  seriously  affected  in  scurvy.  In  their 
scorbutic  animals  the  ground  substance  and  fibroblasts  were  present,  but 
there  was  no  reticulum  nor  collagen  present.  Such  defective  intercellular 
material  has  been  found  in  connective  tissue,  bone  and  teeth.  \\'ithin 
twenty-four  hours  after  the  administration  of  vitamin  C  to  such  scor- 
butic animals  \\'hole  bundles  of  collagen  were  fomied.  Although  the 
capillaries  are  believed  to  be  involved  both  from  the  clinical  and  embry- 
onic points  of  view,  no  such  morphological  lesions  have  been  found. 

In  the  formation  of  bone  and  cartilage  the  intercellular  substance  is 
of  major  importance.  The  lesions  produced  in  these  structures  due  to 
lack  of  vitamin  C  are  similar  to  the  scorbutic  changes  in  other  parts  of 
the  body  and  like  them  are  due  to  a  failure  to  form  intercellular  sub- 
stance. The  anatomical  location  of  these  lesions  depends  to  a  large  extent 
on  two  factors,  growth  and  stress.  This  explains  ^^•hy  bony  lesions  and 
hematomas  are  seen  so  commonly  in  the  child.  These  factors  explain 
further  the  occurrence  of  petechiae  in  either  usual  or  unusual  locations. 
The  frequently  cited  example  of  the  scorbutic  blacksmith,  who  had 
many  petechiae  over  the  shoulders  and  arms,  thus  is  given  an  explanation. 

Gross  changes  in  bone  in  vitamin  C  deficiency  are  seen  most  com- 
monly at  the  costochondral  junctions,  the  distal  end  of  the  femur,  the 
proximal  end  of  the  tibia  and  of  the  humerus  and  the  wrist.  In  the  scor- 
butic state  formation  of  cartilage  and  bone  matrices  soon  ceases.  The 
osteoblasts  are  surrounded  by  liquid,  and  no  collagen  is  to  be  seen.  This 
results  in  the  rarefied  area  at  the  ends  of  the  diaphysis  seen  in  x-rays  (Fig. 
25).  The  Gennans  aptly  termed  this  appearance  "Gerustmark",  frame- 
work marrow,  as  the  strands  of  apparent  connective  tissue  seem  to  be 

Vol.  I.  948 


VITAMIN  C:  PAIHOLOGICAL  PHYSIOLOGY       452(53) 

surrounded  by  a  liquid.  The  osteoblasts  revert  to  their  prototype  in 
scurvy  and  form  a  fibrous  rather  than  a  bony  union  between  the  diaphy- 
sis  and  the  epiphysis,  thus  pemiitting  false  motion  sometimes  in  these 
areas.   The  cortex  of  the  bone  rarefies  and  becomes  very  thin  so  that 


Fig.  25.    X-ray  of  long  bones  in  scurvy. 

fractures  from  trivial  traumata  occur.  The  periosteum  is  only  loosely 
attached  to  the  bone  and  eventually  becomes  stripped  from  the  shell-like 
cortex.  Because  of  the  unyielding  nature  of  the  cortex,  subperiosteal 
hemorrhagres  occur  frequently.  Such  hemorrhages  further  strip  the 
periosteum,  giving  the  picture  so  characteristic  of  the  scorbutic  state. 
Vol.  I.  948 


452(54)  VITAMINS  AND  VITAMIN  DEFICIENCY 

The  response  to  ascorbic  acid  is  dramatic.  Within  a  day  this  sickly 
process  is  reversed,  and  bundles  of  collagen  can  be  seen.  Osteoid  material 
appears  in  a  few  hours  around  the  osteoblasts  with  the  formation  of 
trabeculae  and  the  cessation  of  hemorrhages  from  the  fragile  capillaries. 
In  short,  normal  bone  formation  starts  again.  Vitamin  C  is  also  essential 
for  the  callus  formation  necessary  for  the  healing  of  fractured  bones. 
This  explains  the  obsen^ations  made  in  Lind's  time  of  the  old-healed 
fractures  breaking  down  when  sailors  developed  scurvy. 

Faulty  formation  of  intercellular  substance  in  connective  tissue  is  of 
practical  importance  in  wound  healing.  It  has  been  widely  obser^^ed 
that  in  the  scorbutic  person  minor  abrasions  and  wounds  heal  very 
slowly.  Crandon^"  studied  and  finally  settled  this  problem  by  his  well 
controlled  experiments  on  himself.  For  a  period  of  6  months  he  restricted 
himself  to  a  vitamin  C-free  diet,  supplemented  by  all  the  other  known 
vitamins.  At  the  end  of  the  first  3  months  on  such  a  diet  a  wound  was 
made  on  his  back.  This  wound  healed  well,  and  histological  examination 
showed  ample  intercellular  substance  and  capillary  formation.  After  he 
had  been  on  the  restricted  diet  for  6  months  and  had  had  clinical  scurvy 
for  3  weeks,  a  wound  similar  to  the  first  was  made.  The  skin  healed,  but 
the  wound  beneath  did  not.  Unorganized  blood  clots  filled  the  wound, 
and  histological  study  of  the  tissue  showed  the  same  lack  of  intercellular 
substance  and  capillary  formation  as  was  found  by  W'olbach  in  w^ounds 
of  scorbutic  guinea  pigs.  Crandon  then  received  an  intramuscular  injec- 
tion of  1,000  mgm.  of  ascorbic  acid.  A  biopsy  specimen  taken  from  the 
wound  10  days  later  showed  good  healing  and  ample  intercellular  sub- 
stance. This  observation  shows  that  vitamin  C  is  an  important  factor  in 
the  healing  of  a  wound,  but  the  physician  must  not  lose  sight  of  the  fact 
that  wound  healing  is  dependent  on  many  other  factors. 

The  lesions  appearing  in  the  mouth  in  vitamin  C  deficiency  are  more 
difficult  to  explain.  The  gingiva  is  involved  only  when  teeth  are  present, 
an  observation  that  still  is  without  explanation.  Hess^*^*  was  of  the  opinion 
that  infection  played  a  prominent  role  in  the  gingival  lesions,  but  one  can 
observ^e  gingival  signs  of  scurfy  before  infection  supervenes.  Certainly 
there  is  an  increase  in  the  number  of  capillaries  present,  resultine^  in  con- 
gestion and  swelling  of  the  gums.  These  vessels  are  of  poor  quality  and 
give  rise  to  frequent  hemorrhage.  The  intercellular  substance  of  the 
tissue  itself  is  defective,  and  the  gingiva  becomes  easily  infected  and  sub- 
sequently breaks  down  to  become  ulcerated  and  even  gangrenous.  The 
teeth  themselves  undergo  much  the  same  change  as  does  bone,  the  main 
defect  occurring  in  the  dentine.   There  is  resorption  of  normal  dentine 

Vol.  I.  948 


VITAMIN  C:  PATHOLOGICAL  PHYSIOLOGY       452(50 

beginning  along  Tome's  canals  and  fonnation  of  an  inferior  type  of 
osteodentin  or  of  pulpstone  which  results  from  metaplasia  of  the  dentin- 
forming  cells.  The  pulp  becomes  hyperemic  and  edematous,  and  atro- 
phy and  degeneration  of  the  odontoblast  layer  follow.  There  is  no 
convincing  evidence  that  dental  decay  in  man  is  due  to  ascorbic  acid 
deficiency.  Falling  out  of  the  teeth  in  ascorbic  acid  deficiency  is  the 
direct  result  of  thinning  of  the  alveolar  bone  such  as  occurs  in  other 
bones.  There  still  is  a  conspicuous  lack  of  precise  knowledge  as  to  the 
relationship  between  vitamin  C  and  gingival  and  tooth  disease  in  man. 

That  the  petechial  and  ecchymotic  hemorrhages  of  the  scorbutic 
state  occur  cannot  be  denied.  Stress  plays  an  important  role  in  their 
location,  and  such  lesions  are  found,  where  a  vessel  rides  over  a  bony 
prominence,  or  where  a  belt  has  been  pulled  tight.  The  integrity  of  the 
capillary  wall  has  been  studied  and  morphological  changes  are  wanting. 
A  cement  substance  is  believed  to  fuse  together  the  endothelium  of  the 
capillaries.  However,  connective  tissue  also  surrounds  the  capillary,  and 
very  thin  collagenous  fibers  ensheath  the  endothelium.  It  is  still  unde- 
cided whether  the  connective  tissue  sheath  or  the  endothelial  cement 
substance  is  affected  in  scuny.  The  relationship  of  vitamin  C  to  so- 
called  capillary  resistance  is  indeed  a  knotty  problem.  Crandon^"  found 
that,  even  though  he  had  the  perifollicular  hemorrhages  of  scurvy  over 
his  legs,  the  positive  pressure  test  done  in  the  arm  was  negative. 

With  the  isolation  and  subsequent  synthesis  of  vitamin  C  came  a 
volume  of  reports  that  the  newly  available  vitamin  would  cure  many  of 
the  nonscorbutic  hemorrhagic  diseases.  All  these  claims  have  been  dis- 
pelled, and  it  is  now  established  that  vitamin  C  wall  have  a  favorable 
effect  only  on  the  hemorrhages  of  scorbutic  origin.  Within  the  past 
twelve  years  much  investigation  has  been  carried  out  on  the  permeability 
of  capillaries.  Szent-Gyorgyi  isolated  a  substance,  which  he  called  citrin 
at  first  and  later  vitamin  P.  He  believed  this  new  vitamin  controlled 
capillary  permeability  and  resistance,  and  that  it  was  responsible  for  the 
petechial  hemorrhages  seen  in  scurvy,  but  two  years  later  he  was  unable 
to  obtain  similar  results.  Much  has  been  done  since  then,  and  the  reports 
are  conflicting.  Recently  Shanno''''^  reported  on  the  use  of  rutin  for  the 
treatment  of  increased  capillary  fragility.  He  points  out  that  citrin  or 
vitamin  P  is  an  impure  mixture  of  two  flavone  glucosides,  hesperidin  and 
eriodictyol.  These  two  substances  he  claims  are  physiologically  inert, 
and  that  possibly  the  active  principle  in  citrin  was  rutin.  The  authors 
have  studied  the  relationship  of  abnormal  capillary  fragility,  ascorbic 
acid  deficiency,  vitamin  P  and  rutin  for  years  and  have  not  found  in  their 

Vol.  I.  948 


452(56)  VITAiVIINS  x\ND  MTAMIN  DEFICIENCY 

studies  a  sufficiently  clear  relationship  to  warrant  reporting  their  results. 

In  1930  iMettier,  iMinot  and  Townsend''"  stated  that  anemia  is  found 
commonly  in  adults  with  chronic  vitamin  C  deficiency.  They  concluded 
from  their  studies  that  this  anemia  responded  specifically  when  orange 
juice  was  administered  but  did  not  respond  to  iron  or  purified  liver 
extract.  They  showed  that  the  erythrocytes  were  normocytic,  normo- 
chromic or  moderately  macrocytic,  hyperchromic  in  contrast  to  pre- 
vious teachings  that  the  cells  generally  were  hypochromic.  They  found 
the  bone  marrow  to  be  moderately  hyperplastic  and  normoblastic  prior 
to  therapy.  After  orange  juice  was  administered,  they  noted  an  increase 
in  cellularity  of  the  marrow  due  principally  to  an  increase  in  normo- 
blasts. 

Since  1930  numerous  observers  have  reported  hematological  studies' 
on  persons  with  scurvy.  Much  of  this  work  seems  to  indicate  that  scurvy 
and  anemia  do  not  necessarily  coexist,  that  experimental  vitamin  C  lack 
does  not  interfere  with  blood  formation,  and  that  patients  with  naturally 
occurring^  scurvy  and  anemia  show  erythrocyte  and  hemoglobin  regen- 
eration while  on  a  vitamin  C-free  but  otherwise  adequate  diet.  The  bone 
marrow  has  been  described  variously  as  hyperplastic  with  normoblastic 
maturation  arrest,  as  hypoplastic  and  as  megaloblastic.  In  short,  the 
inference  is  that  vitamin  C  is  not  essential  for  normal  hematopoiesis,  and 
that  hemorrhage,  lack  of  iron  and  some  unknown  vitamin  B  complex  or 
other  deficiency  state  account  for  scorbutic  anemia.  The  experiment  of 
Crandon  mentioned  above  is  worthy  of  note,  for  in  spite  of  blood  loss 
incurred  in  making  various  blood  determinations  he  did  not  develop 
anemia.  The  hemoglobin  started  to  fall  in  the  third  month  but  returned 
to  normal  values  following  the  ingestion  of  ferrous  sulphate  daily.  More 
recently  Lozner^'^  has  shown  that  iron  alone  caused  hemoglobin  regen- 
eration in  patients  with  vitamin  C  deficiency.  It  is  interesting  that 
W'olbach^"  found  in  long-continued  partial  vitamin  C  deficiency  in  the 
E^uinea  pig  that  large  regions  of  bone  marrow  became  devoid  of  blood- 
forming  cells  and  the  seat  of  a  deposit  of  amyloid-like  material.  He 
believed  that  the  anemia  associated  with  the  scorbutic  state  in  the  guinea 
pig  was  a  secondary  phenomenon.  No  such  bone  marrow  deposits  have 
been  found  in  man,  however.  Hence,  to  state  it  mildly,  one  must  say  the 
evidence  in  the  human  being  is  conflicting. 

The  recent  studies  of  \^ilter,  \\'oolford  and  Spies^'"  throw  light  on 
this  problem.  They  studied  carefully  19  cases  of  severe  scurvy  admitted 
to  a  large  municipal  hospital.  Several  features  worthy  of  special  empha- 
sis are  pointed  out  by  these  investigators.  The  general  appearance  of 

Vol.  1.  948 


VITAMIN  C:  PATHOLOGICAL  PHYSIOLOGY       452(57) 

patients  with  severe  scurvy  is  distinctive.  Stasis  cyanosis  in  the  extremi- 
ties, sallow,  dirty  gray,  cadaveric,  skin  color,  somnolence,  letharg^v  and 
hypotension  appear  insidiously  and  are  the  prodromata  of  peripheral 
vascular  collapse  which  may  occur  suddenly  without  further  warning^. 
Cheyne-Stokes  type  of  respiration  occurs  particularly  in  patients  with 
arteriosclerotic  cerebrovascular  disease  and  anemia.  All  of  these  vasomo- 
tor abnormalities  disappear  within  from  24  to  36  hours  after  the  oral  or 
parenteral  administration  of  adequate  amounts  of  vitamin  C.    Although 


M 

gms 

% 

J.H.    AGE   63 

HBC. 

Hb. 

RtTIC 
HEMA! 

VIT.  0  fREE       VIT.  B  COMPLEX   LOW   DIET 

VIT.  C    SOOmg.  DAILY 

Hb. 

40 

12.0 

40 

__ZII 

<55 

J "-'^R.B.C. 

3.0 

9.0 

30 

"^j^^^^^^^rl^HEMATOCRlT 

2.5 

7.5 

25 

^^^7 

2.0 

6.0 

20 

-<^^^ 

1.5 

4.5 

15 

1.0 

3.0 

IC 

y^,,'\ 

0.5 

1.5 

5 

/-"""' 

V, 

*.-.          ,xRETlC. 

o'.o 

SIZt  30  31    6/1    2    J 

4     5      t.      7     e     5     10    11     12    13     14    15    \b 

r    le   19   20  21    22  23  24  25  26  27  28  2»  30 

Fig.  26.  Decline  in  erytlirocytes  and  hemoglobin  in  severe  scurvy  as  clinical 
course  grew  worse  prior  to  vitamin  C  therapy  (from  Jour.  Lab.  and  Clin.  iMed.,  1946, 
XXXI,  609.) 

the  exact  mechanism  responsible  for  these  changes  is  unknown,  it  should 
be  noted  that  in  guinea  pigs  and  rats  a  direct  relationship  has  been  re- 
ported to  exist  between  the  vitamin  C  stored  in  the  adrenals  and  the 
synthesis  of  adrenocortical  steroids. 

The  hematological  data  (Fig.  26)  gathered  from  our  patients  with 
anemia,  while  they  are  subsisting  on  diets  very  low  in  vitamin  C  and  low 
in  the  vitamins  of  the  B  complex,  corroborate  many  of  the  original  ob- 
servations of  A4ettier,  Minot  and  Townsend  using  orange  juice.  Nine  of 
the  critically  deficient  patients  either  did  not  improve  clinically  or 

Vol..  T.  948 


452 (.-S)  VITAMINS  AND  VITAMIN  DEFICIENCY 

heniatologically  or  became  more  anemic  and  debilitated  on  this  diet. 
Striking  hematological  and  clinical  recovery  occurred  after  vitamin  C 
alone  was  added  to  the  experimental  regime,  much  the  same  effect  pre- 
viously reported  for  orange  juice. 

The  authors  have  found  other  patients  with  mild,  moderate  or  severe 
scurvy  and  with  no  anemia.  In  fact  a  normal  blood  picture  has  been 
found  in  12  ambulatory  patients  with  scurvy  who  have  entered  the 
Nutrition  Clinic,  Hillman  Hospital.  Further  observations  from  this  clinic 
indicate  that  many  nutritionally  deficient  persons  repeatedly  have  had 
negative  tests  for  vitamin  C  in  the  plasma  for  as  long  asi  5  consecutive 
years,  and  yet  they  did  not  develop  clinical  scurvy  or  anemia.  The 
factors,  which  cause  the  development  of  anemia  in  some  persons  with 
scur\'y  but  not  in  others,  are  not  understood.  Certain  considerations, 
however,  help  explain  this  variation  in  patients.  In  the  normal  course  of 
events  deficiency  diseases  seldom  occur  as  single  entities.  Deficient  diets 
seldom  are  deficient  in  a  single  essential  factor. 

A  patient  with  severe  vitamin  C  depletion  may  have  no  anemia  until 
additional  strain  is  placed  on  the  bone  marrow  by  a  deficiency  of  protein, 
iron  or  other  unknown  factors  which  may  be  necessary  for  normal 
hematopoiesis.  Yet,  after  the  anemia  has  developed,  the  deficiency  of  the 
latter  factors  may  not  be  serious  enough  to  prevent  a  remission,  when 
large  amounts  of  ascorbic  acid  are  administered.  In  many  deficient  per- 
sons bed  rest,  which  reduces  metabolic  requirement  for  all  essential 
nutrients,  may  be  sufficient  therapy  to  produce  a  clinical  and  hematolog- 
ical remission.  Depending  on  the  interplay  of  multiple  factors,  morpho- 
logical differences  in  blood  and  bone  marrow  and  varied  therapeutic 
responses  may  occur  readily  in  patients  with  scurvy  and  other  deficiency 
states.  For  these  reasons  observations  on  patients,  who  were  critically 
ill  with  scurvy,  anemia  and  other  deficiency  diseases  of  long-standing, 
cannot  be  compared  satisfactorily  with  data  on  human  subjects  in  whom 
a  single  deficiency  state,  scurvy,  has  been  produced  experimentally  with- 
out the  occurrence  of  anemia. 

Symptomatology 

As  for  its  pathological  physiology  the  symptomatology  of  vitamin  C 
deficiency  may  be  described  by  a  summary  of  the  symptoms  of  scurvy. 
Scurvy  is  encountered  most  frequently  in  the  very  young  and  the  very 
old,  but  no  sex,  race  or  age  group  is  exempt.  There  are  certain  points  of 
difference  in  the  scurvy  seen  in  the  young  infant  and  that  seen  in  the 

Vol.  I.  948 


VITAMIN  C:  SYMPTOMATOLOGY  4; :  ( 59) 

adult.  For  sake  of  clarity,  therefore,  an  arbitrary  distinction  is  made,  and 
the  symptomatology  of  these  two  age  groups  is  discussed  separately. 
The  etiology  and  general  pathology  are  the  same,  however,  the  mani- 
festations in  the  one  instance  occurring  in  immature,  rapidly  growing 
tissue  and  in  the  other  instance  in  mature,  slow  growing  tissue. 


Ivfimtile  Scurvy 

The  classical  picture  of  acute,  florid,  infantile  scurvy  is  the  most 
widely  kno\\-n  variety;  yet  it  is  a  picture  we  should  not  allow  to  be  seen 
today.  In  this  neglected,  almost  terminal  state  the  child  cries  out  as  its 
bed  is  approached.  The  afflicted  infant  lies  motionless  on  its  back  with 
one  or  both  thighs  everted  and  flexed  on  the  abdomen.  The  thighs  are 
swollen  and  severely  tender.  To  touch  the  child  anywhere  results  in  a 
cry  of  both  pain  and  horror.  This  type  presents  a  striking  picture  and 
is  not  easily  forgotten.  This  form  of  scur^^y  is  not  the  most  common, 
nor  is  the  practicing  physician  likely  to  see  it.  The  most  common  form 
of  the  disease  generally  is  encountered  in  the  last  half  of  the  first  year. 
The  mother's  presenting  complaint  may  be  that  her  child  is  not  gaining 
weight  properly,  or  that  he  is  unusually  irritable  or  lethargic  and  does 
not  eat  well.  The  infant  appears  pale  and  sallow,  and  the  only  physical 
abnormality  may  be  very  questionable  tenderness  over  the  distal  end  of 
the  femur.'  The  diagnosis  of  scur\^y  in  this  instance  usually  is  based  on 
the  response  to  specific  therapy.  This  is  the  so-called  latent  form  of 
scurvy.  If  treatment  is  not  instituted,  manifest  scuny  develops.  Beading 
of  the  ribs  may  occur  and  thus  complicate  the  picture  by  suggesting  a 
diagnosis  of  rickets.  However,  vitamin  D  fails  to  correct  the  defect. 
Latter,  subperiosteal  hemorrhages  may  result  from  trauma  so  trivial  as 
not  to  be  remembered.  Such  hemorrhages  may  occur  in  the  adult,  but 
it  is  a  rare  finding.  The  resultant  swellings  are  very  tender  and  usually 
will  involve  the  lower  end  of  the  femur  and  the  proximal  end  of  the  tibia, 
although  they  may  involve  other  bones.  Such  hemorrhages  are  seen 
easily  in  the  x-ray.  In  addition  to  subperiosteal  hemorrhages  there  may 
be  hemorrhages  into  the  soft  tissue.  The  hair  follicles  and  sweat  glands 
are  particularly  susceptible.  Again  stress  is  an  important  factor  in  the 
location  of  these  petechiae  and  ecchymoses.  In  many  instances  the  diaper 
is  responsible  for  the  production  of  such  lesions  on  the  inner  aspect  of 
the  thigh.  Gross  hemorrhage  may  occur  elsewhere  as  the  disease  pro- 
i^resses,  s^ivino-  rise  to  epistaxis,  hemoptysis,  bloody  diarrhea  and  occa- 

VOL.  1.  948 


452  (6o)  VITAMINS  AND  VITAMIN  DEFICIENCY 

sionally,  hemothorax.  When  such  hemorrhages  occur  in  abdominal 
organs  or  in  the  brain,  confusing  and  alarming  symptoms  ensue. 

The  lesions  of  the  gums  may  be  so  mild  initially  as  to  be  overlooked. 
They  are  seen  only  when  teeth  are  present.  The  gums  show  a  very  mild, 
peridental  hemorrhage  or  merely  a  border  of  increased  redness  about  the 
tooth.  Later  the  gums  become  swollen  and  purple,  and  as  progression 
occurs,  infection  is  added,  and  the  ulcerated,  fetid  gum  of  the  acute  case 
is  seen. 

In  addition,  the  infant  may  present  early  slight  elevations  of  tem- 
perature, which  become  more  marked  as  the  disease  continues.  A  similar 
slight  increase  in  the  respiratory  rate  may  occur  as  a  result  of  mild  pain 
on  motion  of  the  costochondral  junctions.  The  respiration  thus  may  be 
shallow  and  more  rapid  than  normal. 


Adult  Sc/irvy 

The  initial  symptoms  of  vitamin  C  deficiency  in  the  adult  are  as  ill- 
defined  as  they  are  in  the  child.  After  a  long  period  of  deficiency  of 
vitamin  C,  the  adult  will  develop  symptoms  of  lassitude,  irritability,  easy 
fatigability  and  insidious  weight  loss.  Vague  aches  and  pains  in  the 
muscles  and  about  the  joints  appear  so  as  to  stimulate  "rheumatism".  The 
face  is  pale  and  sometimes  bloated,  the  skin  being  a  dirty  gray,  ashen 
color.  There  may  be  hypotension  and  stasis  cyanosis. 

In  the  absence  of  adequate  therapy  the  symptoms  and  signs  become 
more  marked.  The  muscle  and  joint  pains  become  severe  and  are  the 
result  of  hemorrhage  into  and  around  these  structures.  Large  ecchymoses 
are  frequent,  and  their  color  varies  greatly.  The  more  recent  ones  are 
red,  while  the  older  ones  are  blue,  brown  or  green.  In  addition,  the  well 
known  perifollicular  petechiae  become  evident.  Again  these  symptoms 
and  signs  are  dependent  on  stress  and  lines  of  force.  The  petechial  hem- 
orrhages may  occur  almost  anywhere  in  the  skin  but  are  more  common 
over  the  lower  extremities.  Subungual  hemorrhages  and  splinter  hemor- 
rhages may  occur.  Gross  hemorrhage  may  result  in  epistaxis  and  other 
manifestations  as  listed  under  infantile  scurvy.  Subcon junctional  hemor- 
rhages are  seen  occasionally. 

The  gum  lesions  follow  the  same  pattern  as  in  infantile  scurvy.  In 
some  instances  the  gums  become  so  swollen  and  cons^ested  as  to  cover 
the  teeth  completely,  thereby  making  mastication  a  very  painful  pro- 
cedure. The  teeth  become  loose  and  eventually  may  fall  out. 

Vol.  I.  948 


VITAMIN  C:  DIAGNOSIS  452(61) 

Anemia  is  not  uncommon  in  adult  scurvy,  and  the  complaints  refer- 
able to  this  state  are  the  same  as  for  any  normocytic  anemia.  The  palpi- 
tation, dyspnea  and  cardiac  dilatation,  sometimes  seen,  are  most  likely 
the  result  of  the  lowered  erythrocyte  count  and  consequent  anoxemia. 

As  one  follows  the  sequence  of  events  from  earlv  to  late  scurvy,  it 
becomes  apparent  that  a  correct  and  early  diagnosis  is  very  important  in 
view  of  the  fact  that  the  disorder  is  not  self-limited  and  that  we  possess 
specific  remedies  for  it.  The  diagnosis  may  be  difficult  for  those  who 
have  gleaned  their  information  merely  from  the  textbooks.  Some  per- 
sons with  scurvy  have  been  treated  again  and  again  for  rheumatism. 
Surgeons  must  be  alert  for  signs  of  ascorbic  acid  deficiency  when  they 
perform  an  operation  for  "bone  tumor"  or  "osteomyelitis".  If  the  treat- 
ment is  inadequate,  the  cure  may  be  incomplete,  and  the  disease  persist 
for  years.  At  best  it  probably  takes  months  or  years  before  the  tissues 
return  to  anything  like  their  normal  state  after  treatment. 


Diagnosis 

The  diagnosis  of  vitamin  C  deficiency  in  the  form  of  manifest  scurvy 
in  the  adult  or  in  the  infant  is  not  difficult  for  the  well  trained  physician. 
A  careful  physical  examination  and  a  history  of  an  inadequate  intake  of 
vitamin  C  aid  in  making  a  tentative  diagnosis,  and  x-ray  and  certain 
laboratory  tests  may  add  confirmatory  evidence. 

The  fundamental  hemorrhagic  tendency,  which  results  from  loss  of 
tensile  strength  of  connective  tissue  because  of  alteration  in,  or  lack  of, 
intercellular  substance,  may  appear  in  any  part  of  the  body.  Hemor- 
rhages are  most  likely  to  occur  at  sites  of  stress  due  to  injury,  motion, 
growth  or  infection.  Hemorrhages  of  the  gums  are  common  and  painful. 
In  the  extremities,  where  capillary  pressure  is  high,  and  at  the  site  of  the 
hair  follicles  petechiae  may  appear.  Ecchymoses  are  common.  Hemor- 
rhages may  occur  at  the  joints  and  cause  considerable  pain.  This  may 
result  in  hyperesthesia  on  motion,  which  in  infants  causes  fretfulness  and 
a  motionless,  frog-like  position  of  the  low^r  limbs.  In  the  brain,  intestine 
or  kidney  gross  or  microscopical  hemorrhages  may  occur. 

Skeletal  lesions  lead  to  diagnostic  x-ray  findings.  In  the  infant  or 
child  such  lesions  are  likely  to  occur  at  the  growing  costochondral  junc- 
tions and  at  the  ends  of  the  long  bones  causing  a  characteristic  shelf-like 
costochondral  beading.  The  x-ray  shows  a  zone  of  diminished  density 
which  is  known  as  the  scorbutic  lattice.    The  defective  calcification  at 

Vol.  I.  948 


452(62)  VITAAIINS  AND  VITAMIN  DEFICIENCY 

this  zone  predisposes  to  fracture  with  subperiosteal  hemorrhage  and  slip- 
ping of  the  epiphysis.  Cessation  of  growth  allows  an  intensification  of 
calcijfication  at  the  zone  of  preparatory  calcification  at  the  epiphyseal 
ends  of  the  long  bones  and  at  the  periphery  of  the  epiphyseal  centers  of 
ossification.  In  the  x-rays  these  appear  as  "the  white  lines  of  Frankel" 
Eventually  thinning  of  the  cortex  and  trabeculae  of  the  shaft  gives  the 
bones  a  "ground  glass"  appearance  in  the  x-ray.  In  the  infant  or  in  the 
adult  these  clinical  or  x-ray  signs  of  scurvy  become  apparent  only  after 
some  three  months  or  more  on  a  deficient  diet. 

Some  physicians  are  misinformed  as  to  the  value  of  laboratory  tests 
in  making  a  diagnosis  of  scurvy  as  an  evidence  of  vitamin  deficiency. 
Among  investigators  there  is  considerable  difference  of  opinion  as  to  the 
value  of  the  urinary  excretion  test  and  the  measurement  of  the  whole 
blood  or  plasma  levels  of  ascorbic  acid  in  determining  the  state  of  ascor- 
bic acid  nutrition.  The  authors  use  these  laboratory  tests  only  to  gain 
more  information,  never  to  make  a  diagnosis.  It  is  certain,  however,  that 
the  tissues  are  not  adequately  filled  with  vitamin  C  for  months  before 
clinical  evidence  of  scurvy  appears.  Following  the  administration  of  a 
parenteral  test  dose  of  ascorbic  acid  normal  persons  excrete  approxi- 
mately 80  per  cent,  of  the  total  24  hour  excretion  during  the  first  3  to  5 
hours,  whereas  persons  deficient  in  ascorbic  acid  excrete  much  less. 
Youmans^"^  is  of  the  opinion  that  plasma  values  below  0.4  mgm.  per  100 
c.c.  represent  a  state  of  deficiency  in  which  clinical  signs'  may  appear. 
Crandon,  Lund  and  DilP^^  found  that  low  or  even  zero  findings  may  not 
be  critically  dangerous  unless  maintained  over  a  long  period  of  time. 
W^e  have  observed  patients  who  have  had  zero  values  for  over  5  years 
without  the  appearance  of  a  diagnostic  lesion  of  scurvy.  Nevertheless 
we  are  of  the  opinion  that  important  information  in  respect  to  vitamin  C 
metabolism  can  be  gained  by  determination  of  the  ascorbic  acid  content 
of  the  plasma.  Harris,  Flickman,  Jensen  and  Spies^^^  have  conducted 
extensive  studies  on  nomial  persons  and  on  patients  in  the  Nutrition 
Clinic  in  Birmingham.  They  found  that  the  ascorbic  acid  of  the  plasma 
of  the  patients  was  5  i  per  cent,  of  that  of  the  normal  persons.  The  au- 
thors believe  that  a  level  of  ascorbic  acid  below  0.4  mgm.  per  100  c.c. 
indicates  that  the  reserve  supply  of  ascorbic  acid  is  at  a  danger  point, 
tliat  levels  of  from  0.4  to  0.7  mgm.  per  100  c.c.  indicate  that  the  reserve 
supply  is  low,  and  that  values  ranging  from  0.7  to  1.2  mgm.  per  100  c.c. 
indicate  an  adequate  reserve  supply. 

A  positive  capillary  resistance  test  suggests  a  depletion  of  vitamin  C, 
but  false  positives  frequently  occur  in  the  presence  of  severe  anemia  or 

Vol.  I.  948 


VITAMIN  C:  PREVENTION  AND  TREATMENT    452(63) 

blood  dyscrasla.  Even  in  severe  scurvy  a  negative  capillary  test  some- 
times occurs  so  that  this  test,  in  itself,  cannot  be  considered  as  diagnostic 
of  scurvy. 

If  a  diagnosis  of  scurvy  is  in  doubt,  a  therapeutic  test  is  recommended; 
250  mgm.  of  ascorbic  acid  should  be  administered  parenterally,  while  the 
patient  is  kept  on  his  usual  routine.  Then,  he  should  be  watched  care- 
fully for  any  alteration  of  symptoms. 

Prevention  and  Treatment 

That  fresh  fruits  and  vegetables  are  of  great  value  in  the  protection 
against,  and  in  the  cure  of,  vitamin  C  deficiency  is  every  day  knowledge. 
Mtamin  C  is  present  in  all  living  tissue,  but  fresh  fruits  and  plants  are  the 
best  sources  (Fig.  27).  Rose  hips,  haws,  currants,  strawberries,  cabbage, 
tomatoes  and  the  citrus  fruits  are  the  richest  sources.  Potatoes,  spinach 
and  turnips  are  good  sources.  Many  people  depend  on  the  potato  for 
their  quota  of  ascorbic  acid  by  eating  it  daily  in  large  amounts.  One  half 
pound  of  potatoes  supplies  about  30  mgm.  of  ascorbic  acid,  an  amount 
which  is  considered  adequate  to  protect  against"  scurvy.  The  amount  of 
vitamin  C  in  fresh  fruits  or  vegetables  varies  widely  depending  on  ma- 
turity, time  of  picking,  variety,  season  and  soil. 

Beo-innine  in  the  second  week  of  life  the  infant  should  be  sfiven  i  to  2 
teaspoons  of  fresh  orange  juice  daily  or  25  mgm.  of  ascorbic  acid.  The 
amount  should  be  increased  to  2  ounces  by  the  time  the  child  is  3  months 
of  age  and  to  3  ounces  by  the  age  of  5  months.  Other  citrus  fruits  may 
be  substituted  for  oranges,  but  when  tomato  juice  is  used,  large  amounts 
should  be  given.  If  fruit  juices  are  not  tolerated,  25  to  50  mgm.  of 
ascorbic  acid  should  be  given  daily.  At  least  3  ounces  of  orange  juice, 
comparable  amounts  of  citrus  fruits  or  tomato  juice  or  50  to  100  mgm. 
of  ascorbic  acid  should  be  taken  daily  by  the  average  adult.  Larger 
amounts  of  these  materials  are  indicated  during  pregnancy  and  lactation. 

Scurvy  which  is  due  to  vitamin  C  deficiency  may  be  treated  by  ad- 
ministering ascorbic  acid  orally  or  by  injection.  Parenteral  administra- 
tion is  about  twice  as  effective  per  unit  of  weight  as  is  oral  administration 
and  is  indicated  always  in  stupor  or  coma,  or  where  there  is  difficulty  in 
absorption  from  the  alimentary  tract.  Ascorbic  acid  is  rfeadily  soluble 
and  may  be  added  to  sterile  saline  solution  or  to  5  per  cent,  glucose  solu- 
tion. Because  it  is  too  strong  an  acid  to  be  injected  intramuscularly, 
sodium  bicarbonate  should  be  added  as  a  neutralizing  agent  to  solutions 
for  intramuscular  injection.  For  intravenous  injections  neutralization  is 

Vol.  I.  948 


45^(64) 


MTAAIINS  AND  VITAMIN  DEFICIENCY 


unnecessary.  It  should  be  mentioned  that  ascorbic  acid  i^  excreted  more 
rapidly  following  intravenous  than  intramuscular  injection.    Ascorbic 

FOODS  AS  SOURCES  OF 

ASCORBIC  ACID 

(vitamin  c) 

tn  addition  to  citrus  fruits  and  tomatoes  many  common  fruits  and 
vegetables  supply  significant  amounts  of  ascorbic  acid,  especially  if  eaten 
raw.  This  vitamin  is  readily  destroyed  by  heat  and  it  is  extracted  by  water. 

CONTRIBUTION  OF  SELECTED  SERVINGS  OF  A  FEW  FOODS  AS 
PERCENTAGES  OF  ADULT  MALE  ALLOWANCE  (75  MILLIGRAMS  ) 

0  25%  SO»/o  75%  100* 


GRAPEFRUIT  i'/zav) 
STRAWBERRIES 
ORANGE  (I  av) 

CANTALOUPE    V'z  av) 
CABBAGE  (raw) 
TURNIPS 
SWEET  POTATO 
POTATO   (baked) 
TOMATO  JUICE 
AVOCADO 
WATERMELON 
PINEAPPLE  JUICE 

POTATO    I  American  fried) 

LETTUCE 

BANANA 

PEACH 

APPLE 

PEAR 


^^^^^! 

Hn^ 

1 

32rT,g 
Omg 
mg 

4o7    ^H^a^  * 

<:.,    ^^HHa    7"; 

i.,       ^^^i   M„, 

y'/ynr     ^^^^^KM     71  mn 

4o2  ^^m 

Boz    ■iHI4 

2oz     ^^Hllma 
3'^zo2  ^105 

3''2oz  aa  Smg 
4'ioz   a   4mg 
3oz       i    3mg 

165  mg 
16  mg 
mg 

mg 

Fig.  27.     Foods  as  sources  of  ascorbic  ;icid   (\'itaniin  C). 

acid  has  a  very  low  toxicity.  The  authors  frequently  have  injected  i,ooo 
mgm.  or  given  5,000  mgm.  by  mouth  without  any  ill  effects.  It  is  very 
important  to  continue  intensive  therapy  until  all  the  lesions  are  healed 
and  then  give  a  daily  maintenance  dose  of  50  to  100  mgm.  orally. 

It  should  be  emphasized  that  the  present  knowledge  is  so  meager  tnat 
a  precise  statement  of  what  constitutes  proper  dosage  is  not  practicable. 
Since  vitamin  C  deficiency  is  frequently  a  part  of  mixed  deficiency 
diseases,  it  is  not  enoug-h  to  insure  an  adequate  intake  of  vitamin  C  alone. 
In  Figitre  28,  showing  the  contrast  between  the  nutrients  supplied  by 

Vol.  I.  948 


VITAMIN  C:  PRE\  ENTION  AND  TREATMENT    452(65) 

dietaries  of  children  witli  deficiency  diseases  and  the  allowance  recom- 
mended, the  degree  of  deficiency  of  other  essential  nutrients  which 
remain  after  the  deficiency  of  vitamin  C  is  shown  clearly. 

The  other  vitamin  deficiencies  associated  with  many  cases  of  scurvy 
should  be  searched  for  and  treated.  An  excellent  diet  should  be  given 
always,  and  additional  specific  therapy  should  be  given  also  and  con- 
tinued until  all  evidence  of  vitamin  C  deficiency  has  disappeared.  When 

A/C/rfi/£A/r3    3UPPL/£D    BY  D/^TAfi/fS 

0/=  C/i/LDfif/^">    W/TH    D£/=/C/£NCY    D/3£AS£S 

COA/r/iASTfD   TO  A£COMM£A/DfD  AllOWANCfS  OF  A/UTfi/fAfTS 


paoTciN      cALOHjes     calcium        iron       vitamin  a     thiamins    maonAviN   niacin  AscoxaicAcio '" 

a         Al/oin/ance     of    /icr/^r/en/s    recommen&ec/    by    Counci/  on    Fooc/s  one/  A/u/r/Z/on, 
lVo//ono/  Research  Counci/. 

■         Nu/rien/3    -supp/iec/  by    c//e/o/-/es    o/  c/>//c/ren   (v//A    c/o//cienci/    c//seoses. 
Boiec/  on  cZ/e/or/es    of    SO    c/)//c/ren   ivi/h  c/e/iciency  d/seass3. 
3/uc/y    n^oc/e    c/<y/-/ng    noon//>    d-f    /Worcb. 

Oranges    anc/   grope  fru//     supp/ied  in     overobunc/once    c/uring    /his  period   lync/sr 
•Surplus     Commoc/i/y     P/an. 

Fig.  28.     Nutrients  supplied  by  dietaries  of  children  with   deficiency  diseases  con- 
trasted to  recommended  allowances  of  nutrients. 


(1) 
(2) 


gingivitis  is  present,  mouth  washes  should  be  prescribed,  and  splints  for 
the  legs  should  be  applied  when  indicated. 

The  response  to  adequate  therapy  with  ascorbic  acid  is  dramatic. 
Bone  tenderness  decreases,  purpura,  begins  to  fade,  gums  improve,  appe- 
tite increases  and  loss  of  apprehension  occurs  within  24  hours  after  suffi- 
cient amounts  are  administered  by  the  parenteral  route.  A  similar  striking 
improvement  follows  adequate  oral  therapy.  The  general  treatment 
should  be  directed  toward  restoring  the  patient  to  a  state  of  perfect 
nutrition. 

Vol.  I.  948 


452(66)  VITAMINS  AND  VITAMIN  DEFICIENCY 

VITAMIN  Bi 
(THIAMINE) 

History 

The  modern  era  of  the  study  of  vitamin  Bi  was  initiated  by  Eijk- 
man'",  who  induced  polyneuritic  symptoms  in  fowls  fed  a  diet  of 
polished  rice.  When  they  were  fed  unpolished  rice,  they  did  not  develop 
the  disease,  and  rice  polishings  relieved  the  afflicted  birds.  Grijns^'*  con- 
cluded that  human  beriberi  and  avian  polyneuritis  resulted  from  a  lack 
of  the  same  substances  in  the  rice  bran,  but  physicians  and  other  scientists 
still  were  not  impressed.  It  was  not  until  Fletcher^'-'  and  Eraser  and 
Stanton'*"  established  the  fact  that  unpolished  grain  would  aid  in  pre- 


Fig.  zy.     Crj'stalline  tliiamine  chloride  hydrochloride  (courtesy  of  Merck  and  Co.) 

venting  beriberi  that  serious  consideration  was  given  to  these  theories. 
Funk'"^  made  a  concentrate  of  the  active  principle  in  rice  polishings  and 
thought  he  had  isolated  the  antiberiberi  vitamin.  His  coinage  of  the 
word  "vitamine"  was  very  fortunate  in  that  it  caught  the  imagination  of 
many  for  the  first  time.  In  191 3  Vedder  and  Williams^*'  concentrated 
the  factor  from  rice  polishings  and  showed  that  it  was  dialyzable  and 
absorbed  it  on  charcoal.  SeidelP*^  made  the  important  contribution  that 
it  could  be  adsorbed  on  fuller's  earth  and  removed  with  alkali,  and 
Peters'^^  introduced  still  more  refinements.  A  milestone  in  the  isolation 
was  passed  in  1926  when  Jansen  and  Donath''^^  successfully  isolated  the 
pure  vitamin  for  the  first  time.  The  final  word  in  the  chapter  was  written 
brilliantly  by  \\'illiams  and  his  schooP**^  when  they  synthesized  the  vita- 
min in  1936.  Throughout  the  scientific  world  the  names  of  Takaki, 
Vol.  I.  948 


VITAMIN  Bi:  CIIEMIS  1 RY  AND  PI  lYSlOLOGY      452(67) 

Eijkman,  Funk,  Vedder,  Grijns,  Williams,  Peters,  Clinc,  \\'estenbrink, 
Jansen,  Seidell,  Sinclair,  Waterman  and  many  others  are  held  in  reverent 
esteem  as  contributors  of  important  knowledge  of  vitamin  Bi. 

Chemistry  and  Physiology 

Vitamin  Bi  (thiamine)  is  a  white  crystalline  compound  (Fig.  29) 
which  is  prepared  synthetically  as  the  hydrochloride  (Fig.  30).  The 
properties  of  the  natural  and  the  synthetic  compound  are  identical.  The 

N=CNH,HCI       S"^ 

II  '  " 

C^=C — C — CH,OH 
I  /  I  H 

HxC— C      C— CH,— N 

I    II  IV-i 

N  — CH  CI     H 

Fig.  30.    Structural    formula    of    thiamine    chloride    hydrochloride. 

hydrochloride  melts  at  248  to  250°  C.  and  is  very  soluble  in  water.  It  is 
stable  at  100°  C.  in  acid  solution  but  is  destroyed  at  100°  C.  in  neutral 
or  alkaline  solution. 

Vitamin  Bi  is  important  in  tissue  oxidation  of  carbohydrate  com- 
pounds. Apparently  it  acts  as  a  compound  capable  of  reversing  oxidation 
and  reduction.  \'itamin  Bi  represents  the  reduced  form  and  can  be 
oxidized  to  a  disulfide,  the  oxidation  occurring  under  physiological  con- 


CHj  O 

=  CNHi 

I  C  =  CCHaCHaO P O P OH 

CHjC  CCHe n/'  I  I  I 

II  I   ^CH  — S  OH  OH 
—  CH               X 


PHOSPHORIC     ACID    ESTER    OF    THIAMINE    (COCARBOXYL ASE) 

Fig.  31.    Structural  formula  of  phosphoric  acid  ester  of  thiamine  (cocarboxylase). 

ditions.  The  disulfide  shows  full  vitamin  activity.  The  disulfide  can  be 
reduced  to  the  thiol  form  by  hydrogen,  hydrogen  sulfide,  glutathione 
and  other  substances. 

Yeast  contains  a  specific  catalyst  called  carboxylase,  which  decar- 
boxylates  pyruvic  acid  as  is  shown  below. 

Vitamin  Bi— pyrophosphate 
CH3.CO.  COOH ^  CHs.  CHO+CO. 

Vol.  I.  948 


452(68)  VITAMINS  AND  VITAMIN  DEFICIENCY 

The  coenzyme  of  this  reaction  is  the  phosphoric  acid  enzyme  of  thia- 
mine, cocarboxylase.  It  has  been  synthesized  enzymatically  and  by 
chemical  methods,  and  Lohman  and  Schuster^^^  proved  that  it  was  the 
pyrophosphate  of  vitamin  Bi.  The  action  of  vitamin  Bi  in  the  body  is 
due  partly  or  mainly  to  the  action  of  cocarboxylase  (Fig.  31).  The  liver 
transforms  much  of  the  vitamin  Bi  into  cocarboxylase,  and  it  also  can 
hydrolyze  cocarboxylase  to  form  vitamin  Bi.  The  kidney  phosphory- 
lates  thiamine. 

It  appears  then  that  vitamin  Bi  in  the  body  acts  as  an  acceptor  for 
such  substances  as  adenosin-triphosphoric  acid.  The  carboxylase  system 
consists  of  a  specific  protein  and  the  coenzyme,  the  cocarboxylase,  and 
the  metal  ions.  Manganese,  magnesium  and  iron  are  stimulants,  and  zinc, 
calcium,  nickel  and  cobalt  retard  in  small  concentration.  Presumably 
the  metal  element  in  the  enzyme  acts  as  a  cement  substance  binding 
protein  to  cocarboxylase.  The  chemical  reactions  of  cocarboxylase  re- 
semble closely  those  of  vitamin  Bi.  The  molecular  weight  of  the  protein 
particle  of  cocarboxylase  is  not  known,  but  it  is  estimated  to  be  150,000. 
The  vitamin  action  occurs  as  a  result  of  the  specific  structure  of  the 
molecule.  The  different  salts  of  the  vitamin  have  a  corresponding  activ- 
ity. Structural  alterations  are  followed  by  a  disappearance  of  vitamin 
actions.  The  pyrimidine  ring,  the  thiazole  ring  and  the  methylene  bridge 
between  them,  an  unsubstituted  amino-group  in  4-position  of  the  pyrimi- 
dine ring,  the  5-hydroxy-alkyl-group  and  free  2 -4-position  in  the  thia- 
zole nucleus  are  necessary  for  the  vitamin  action. 

\^itamin  Bi  is  widely  distributed  in  raw  foodstuffs.  The  richest 
sources  are  whole  cereals,  yeast  and  pork.  Yet  even  these  foods  do  not 
contain  a  great  abundance  of  the  vitamin.  During  the  preparation  of 
food  for  consumption  much  of  the  vitamin  is  lost.  Heat  destroys  some, 
and  since  the  vitamin  is  water-soluble,  considerable  is  lost  in  discarding 
the  water  in  which  food  is  cooked.  Discarding  the  bones  of  meat  and 
the  peelings  and  cores  of  fruit  also  accounts  for  some  of  the  loss  which 
occurs  during  the  preparation  of  food.  Vegetables  are  not  rich  in  thia- 
mine, but  they  are  important  sources  because  they  are  inexpensive.  In 
the  average  diet  approximately  25  per  cent,  of  the  total  thiamine  is  ob- 
tained from  cereals  or  cereal  products.  Unenriched  white  flour  contains 
little  thiamine  as  contrasted  with  whole  wheat  fiour,  only  about  one- 
tenth  of  the  amount  originally  present  in  the  whole  wheat.  Legumes, 
nuts,  sugar  cane,  molasses  and  whole  commeal  are  all  rich  in  vitamin  Bi. 

Man  cannot  synthesize  thiamine,  nor  can  he  store  it  to  any  great 
degree.    The  highest  concentration  is  in  the  liver,  kidney,  heart  and 

Vol.  I.  948 


VITAMIN  B,:  CHEMISTRY  AND  PHYSIOLOGY      452(69) 

brain.  The  greater  part  of  the  total  body  store  is  in  the  Hver  and  muscles. 
On  a  diet  deficient  in  thiamine  the  amount  stored  declines  rapidly  at  first, 
then  more  slowly,  and  the  last  traces  are  held  most  persistently.  Mucli 
work  is  being  done  on  the  excretion  of  thiamine,  and  there  is  a  great  need 
to  know  more  of  its  distribution  in  tissues. 

An  excess  intake  of  thiamine  is  wasted  chiefly  by  excretion  from,  or 
destruction  in,  the  body.  Only  a  small  percentage  of  the  intake  from  a 
diet  rich  in  vitamin  Bi'is  excreted  in  the  urine,  but  the  kidney  concen- 
trates it  from  the  plasma  to  a  marked  degree,  twenty  times  or  more.  The 
fecal  output  is  relatively  small  but  fairly  constant.  At  the  present  time 
our  knowledge  of  the  importance  of  thiamine  excretion  in  the  sweat  rests 
on  evidence  too  slender  to  be  interpreted.  We  can  be  certain  that  in 
human  beings  and  in  animals  the  total  amount  excreted  decreases  with 
restriction  of  the  vitamin  in  the  diet. 

Piatt  and  Lu'''  have  shown  that  the  bisulfite-binding  power  of  the 
blood  is  increased  in  human  beings  with  thiamine  deficiency.  This  deter- 
mination is  not  entirely  specific  for  pyruvic  acid,  since  any  aldehyde  or 
ketone  group  also  would  give  positive  tests.  Nevertheless,  in  vitamin  Bi 
deficiency  a  part  of  the  bisulfite-binding  substance  has  been  identified 
definitely  as  pyruvic  acid.  In  addition  to  lactic  acid,  methyl  glyoxal  has 
been  found  in  the  blood  of  persons  with  beriberi.  Glyoxal  is  pyruvic 
aldehyde  and  is  a  stage  of  oxidation  of  the  terminal  carbon  atom,  whereas 
lactic  acid  is  the  result  of  incomplete  oxidation  of  the  central  carbon 
atom. 

Lewy,  Spies  and  Aring^''  gave  by  injection  50  mgm.  of  synthetic 
cocarboxylase  to  patients  with  nutritional  peripheral  neuritis  and  ob- 
served that  the  under-excitable  nerve-muscle  apparatus  was  restored  to 
normal  excitability  within  one  to  four  hours.  This  finding  indicates  that 
a  great  number  of  the  nerve  fibers  were  anatomically  intact,  although 
they  were  unable  to  respond  properly  due  to  the  altered  metabolism. 
In  all  the  patients,  who  received  only  a  single  injection,  and  who  con- 
tinued to  eat  a  diet  deficient  in  thiamine,  the  nerve-muscle  mechanism 
returned  to  its  poorly  functioning  state  within  a  few  days.  Another 
injection  of  either  cocarboxylase  or  thiamine  again  relieved  these  patients. 
The  more  severely  affected  muscles  remained  underexcitable  following 
a  single  injection,  which  probably  means  that  too  many  of  their  fibers 
were  morphologically  damaged  to  permit  prompt  restoration  of  func- 
tion. These  observations  support  the  concept  that  the  early  stage  of  the 
clinical  deficiency  state  is  characterized  by  a  biochemical  rather  than  an 
anatomical  lesion.  These  investigators  studied  the  thiamine  excretion  in 
Vol.  I.  948 


452(70)  VITAiMlNS  AND  VITAMIN  DEFICIENCY 

the  urine  of  these  patients.  It  was  learned  that  the  patients  retained  much 
more  of  the  injected  cocarboxylase  than  did  the  normal  controls.  The 
bisulfite-binding  substance  decreased  in  the  patients,  who  retained  the 
cocarboxylase,  and  the  same  patients  showed  electrical  and  clinical  im- 
provement, which  suggests  an  association  between  these  factors.  It  may 
be  well  to  stress  that  the  degree  of  neuropathy  seen  in  the  south  of  the 
United  States,  where  Lewy,  Spies  and  Aring  were  working,  cannot  be 
compared  to  the  severe  forms'  of  neuropathy  seen  in  many  clinics  in 
association  with  long-standing  and  heavy  addiction  to  alcohol. 

Vitamin  Bi  plays  an  important  part  in  carbohydrate  metabolism. 
Glucose  is  not  oxidized  directly  in  the  body  but  is  transformed  into  CO2 
and  H2O  in  a  number  of  stages.  Two  of  the  intermediate  products  are 
lactic  acid  and  pyruvic  acid.  It  is  thought  that  vitamin  Bi  in  its  phos- 
phorylated  form,  cocarboxylase,  acts  as  a  specific  catalyst  in  breaking 
down  pyruvic  acid.  Pyruvic  acid  and  lactic  acid  are  increased  in  the 
blood  and  in  the  urine  of  vitamin  Bi  deficient  patients  and  animals. 
Peters^^"  has  shown  that  the  brains  and  kidneys  of  avitaminotic  pigeons 
have  a  diminished  oxygen  uptake.  Himwich,  Spies,  Fazekas  and  Nesin^''^ 
have  shown  that  the  neurological  lesions  probably  are  due  to  an  inability 
of  the  vitamin  Bi  deficient  patient  to  oxidize  glucose  efficiently.  These 
investigators  were  concerned  about  the  cerebral  metabolism  of  patients 
who  had  pellagra  with  or  without  clinical  vitamin  Bi  deficiency.  They 
reasoned  that  because  the  brain  oxidized  carbohydrate  chiefiy,  any  alter- 
ation in  carbohydrate  metabolism  resulting  from  a  deficiency  of  thiamine 
should  be  observed  more  readily  in  the  brain  than  in  any  other  organ 
which  was  capable  of  oxidizing  fat  as  well  as  carbohydrate.  The  carbo- 
hydrate metabolism  was  studied  by  measuring  the  differences  between 
the  oxygen,  glucose  and  lactic  acid  of  the  arterial  blood  and  that  of  the 
internal  jugular  vein.  They  found  that  the  average  oxygen  utilization 
for  the  pellagrin  free  of  any  evidence  of  clinical  thiamine  deficiency  was 
6.16  volumes  per  cent.  The  average  for  those  pellagrins  with  clinical 
thiamine  deficiency  was  4.6  volumes  per  cent.  The  average  for  the  entire 
group  was  5.8  volumes  per  cent.  The  normal  subjects  had  excellent 
health  with  no  evidence  of  pellagra,  beriberi  or  any  deficiency,  and  they 
had  a  value  jof  7.4  volumes  per  cent.  It  seemed  that  a  diminution  of  brain 
metabolism  would  best  explain  these  findings.  Correlated  with  this 
diminished  oxygen  uptake  is  the  average  glucose  utilization  of  6  mgm. 
per  100  c.c.  No  difference  in  utilization  of  lactic  acid  was  noted  between 
arterial  and  venous  blood  going  to,  and  coming  from,  the  brain.  These 
observations  afford  a  basis  for  the  explanation  of  the  mental  changes 

Vol.  I.  948 


VITAMIN  Bi:  PATHOLOGICAL  PHYSIOLOGY      452(71 ) 

observed  in  patients  subsisting  on  an  unbalanced  high  carbohydrate  diet. 

It  is  known  that  vitamin  Bi  is  essential  for  the  normal  functioning  of 
the  alimentary  tract,  but  as  yet  we  do  not  understand  the  exact  mech- 
anism by  which  it  functions  in  predisposing  to  gastrointestinal  disturb- 
ances. In  experimental  animals  and  in  human  beings  anorexia,  which  is 
an  early  symptom  of  a  deficiency  of  thiamine,  disappears  promptly 
following  the  administration  of  thiamine.  Boith  the  thiamine  deficient 
animal  and  man,  follo\\ing  the  administration  of  thiamine,  will  eat  food 
which  they  previously  have  refused.  Controlled  studies  with  thiamine 
have  shown  that  the  normal  tone  of  the  alimentary  tract  is  altered  in 
persons  with  thiamine  deficiency.  It  has  been  observed  that  persons  with 
early  thiamine  deficiency  usually  have  little  appetite  and  often  are  con- 
stipated. Gastrointestinal  series  frequently  show  "puddling"  of  the 
barium  in  the  small  intestine.  Some  of  these  persons  improve  impres- 
sively following  the"  administration  of  vitamin  Bi.  It  is  certain,  however, 
that  neither  lack  of  appetite  nor  constipation  are  in  any  way  specific 
manifestations  of  vitamin  Bi  deficiency  in  human  beings.  The  break- 
down in  metabolism  is  primary  and  has  a  widespread  effect  on  all  the 
cells,  and  the  effects  are  not  equally  distributed  in  the  body.  Eventually 
this  failure  to  metabolize  nutrients  by  the  tissue  cells  halts  many  proc- 
esses, and  we  then  find  loss  of  appetite  while,  as  Peters  graphically  states, 
there  is  internal  hunger  in  the  tissues. 

Vitamin  Bi  is  an  essential  factor  for  the  normal  growth  of  the  young 
and  for  the  maintenance  of  normal  health  for  the  adult.  It  is  particularly 
important,  however,  for  the  physician  to  realize  that  several  factors  oper- 
ate concomitantly  and  that  thiamine  alone  is  not  adequate  to  insure 
proper  growth.  \^itamin  Bi  deficiency  often  is  associated  with  loss  of 
libido  in  human  beings  and  experimental  animals.  There  is  a  great  need 
for  vitamin  Bi  during  pregnancy  and  lactatidn.  The  vomiting  of  preg- 
nancy is  common,  and  this  in  itself  may  be  associated  wkh  a  deficiency 
of  vitamin  Bi,  or  it  may  lead  ta  further  vitamin  Bi  deficiency.  Mothers, 
who  have  vitamin  Bi  deficiency,  predispose  their  nursing  infants  to  thia- 
mine deficiency. 

Pathological  Physiology 

\^itamin  Bi  deficiency  affects  the  cardiovascular  system,  and  the 
most  common  cause  of  sudden  death  from  thiamine  deficiency  is  acute 
cardiac  failure.  The  heart  is  dilated  and  enlarged  in  the  classical  case. 

It  is  of  great  interest  that  experimental  deficiencies  rarely  result  in 
serous  effusions  and  cardiac  enlargement,  whereas  in  human  beings  they 

Vol.  I.  948 


452(72)  VITAMINS  AND  VITAMIN  DEFICIENCY 

are  not  uncommon  in  the  acute  case  of  beriberi.  There  is  httle  doubt 
that  cases  of  beriberi  disease  and  cases  of  serous  effusion  have  de- 
veloped on  a  diet  low  in  thiamine  and  that  the  administration  of  thiamine 
will  relieve  the  symptoms.  Still,  investigators  have  been  unable  to  place 
this  on  an  experimental  basis  whereby  the  experimental  subject  eats  a 
vitamin  Bi  deficiency  diet  and  an  inevitable  sequence  of  cardiovascular 
disturbances  occurs. 

The  lesions  of  experimental  vitamin  Bi  deficiency  appear  identical 
with  those  occurring  in  vitamin  Bi  deficiency  in  man,  and  the  majority 
of  investigators  regard  experimental  vitamin  Bi  deficiency  in  animals 
as  a  disease  analogous  to  this  deficiency  in  man.  Degeneration  of  the 
nervous  system  occurs  in  most,  if  not  all,  species  with  prolonged  thia- 
mine deficiency.  Experimental  polyneuritis  in  fowls  is  very  similar  to 
dry  beriberi  in  man,  most  of  the  degeneration  occurring  in  the  peripheral 
nerves.  The  sciatic  nerves  are  especially  involved.  Vedder  and  Clark^^^ 
have  shown  that  in  both  man  and  animals  there  is  evidence  of  involve- 
ment of  every  fiber,  although  the  extent  of  degeneration  is  tremendously 
variable  in  the  fibers  of  the  same  nerves.  The  myelin  degeneration  may 
affect  the  peripheral  nerves,  the  ventral  and  dorsal  nerve  roots  and  the 
tracts  of  the  spinal  cord,  the  medulla,  pons,  midbrain  and  the  internal 
capsule. 

Symptomatology 

Various  clinical  forms  of  vitamin  Bi  deficiency  are  described.  Each 
case,  however,  presents  great  individual  variations.  In  the  adult  the 
onset  usually  is  insidious.  The  symptoms  are  characterized  by  cardio- 
vascular disturbances,  neuritis  and  edema,  and  these  forms  sometimes 
are  termed  "cardiac,"  "neuritic"  or  "wet"  according  to  the  prevailing 
symptoms. 

The  clinical  picture  is  one  of  symmetrical  peripheral  neuritis,  which 
is  the  most  common  finding  and  is  associated  with  weakness,  cramps  in 
the  legs  and  paresthesias  and  burning  sensations  over  the  soles,  dorsum  of 
the  foot  and  ankle.  The  Achilles  and  patellar  refiexes  in  the  typical  case 
are  hyperactive  early  in  the  disease  and  later  are  absent.  The  weakness 
spreads  up  the  legs,  and  the  affected  muscles  become  tender  and  numb. 
Atrophy  of  the  muscles  and  skin  follows.  (Fig.  32)  The  upper  extrem- 
ities frequently  become  involved  in  the  very  severe  cases,  the  hands  and 
arms  being  affected  first.  Burning,  numbness  and  weakness  may  be  fol- 
lowed by  wrist  drop.  The  muscles  of  the  trunk  and  diaphragm  may 
become  involved.  When  edema  is  present,  it  begins  in  the  feet  and  legs 

Vol.  I.  948 


VITAMIN  Bi:  SYMPTOMATOLOGY  452(73) 

and  ascends  up  the  body  and  may  mask  the  muscle  wasting.  Anorexia, 
diarrhea  and  vomiting  may  be  associated  with  it.  Aphonia  sometimes  is 
seen  in  the  adult,  and  in  infantile  vitamin  Bi  deficiency  it  is  a  common 
finding. 

Although  severe  mental  symptoms  usually  do  not  develop,  memory 
difficulties  and  anxiety  states  are  common  and  frequently  are  distressing 


m  ' 

Fig.  32.    Bilateral  marked  atrophy  of  muscles  of  leg  and  feet;  foot  drop  is  evident. 
Case  of  vitamin  Bi  deficiency. 

to  the  patient  and  his  relatives.  Investigators"'^  have  learned  that  there 
is  an  amazing  uniformity  of  the  mental  symptoms  which  have  little  con- 
nection with  the  personality.  The  symptoms  may  be  grouped  as  follows: 

A.  The  Elementary  Syndrome: 

1.  Psycho-sensory  disturbances 

2.  Psycho-motor  disturbances 

3.  Emotional  disturbances 

B.  General  Symptoms  of  the  Central  Nervous  System: 

1 .  \\'eakness  and  increased  fatigability 

2.  Sleeplessness 

3.  Headache 
Vol.  1.  948 


452(74)  VITAMINS  AND  VITAMIN  DEFICIENCY 

The  first  group  of  symptoms  resembles  those  which  may  be  found 
in  diseases  of  the  basal  ganglia  and  thalamus,  while  the  second  group 
represents  general  symptoms  which  usually  accompany  any  disturbance 
of  the  central  nervous  system.  The  complaints  and  responses  to  therapy 
are  practically  identical,  whether  the  personality  is  simple  or  complicated, 
or  whether  the  patient  is  illiterate  or  educated.  Often  there  is  a  "break- 
down of  personality"  during  the  early  stages  of  developing  deficiency. 

Detailed  studies^^^  of  the  emotional  disturbances  in  persons  with  vita- 
min Bi  deficiency  confirmed  the  findings  that,  in  addition  to  the  disturbed 
emotional  reactions,  there  \\'as  some  impairment  of  the  intellectual  and 
cognitive  functions.  Patients  "jumped  at  the  slightest  sound"  or  "cried 
over  the  least  little  thing".  No  alteration  in  the  electroencephalograms 
has  been  demonstrated  despite  the  fact  that  within  a  short  time  after  the 
injection  of  thiamine  the  symptoms  subsided.  Injections  of  saline  given 
in  a  similar  manner  did  not  produce  any  relief.  These  emotional  symp- 
toms may  occur  in  patients  without  deficiency  disease,  however,  and  the 
authors  recommend  thiamine  therapy  only  when  such  symptoms  are 
associated  with  a  deficiency  state. 

Cardiovascular  symptoms  frequently  are  associated  with  fulminating 
acute  types  of  thiamine  deficiency  known  as  "acute  pernicious  beriberi 
heart".  If  associated  with  edema  it  is  called  "wet"  beriberi.  Many 
patients  die  suddenly  from  "beriberi  heart".  The  original  cases  described 
by  Wenckenbach  and  other  clinicians  in  the  Orient  are  characterized 
chiefly  by  right-sided  failure.  A\'eiss  and  AA^ilkins^'^^  and  the  clinicians  at 
the  University  of  Cincinnati  have  examined  a  considerable  number  of 
patients  with  beriberi  heart  disease,  and  the  majority  did  not  have  right- 
sided  failure. 

Infantile  vitamin  Bi  deficiency  usually  occurs  among  infants  in  the 
first  three  months  of  life,  and  the  onset  is  rapid.  The  very  early  symptoms 
usually  are  vomiting  and  a  distaste  for  food.  Attacks  of  pain  frequently 
occur  and  result  in  the  body's  beinor  held  rigrid  although  true  convulsions 
do  not  appear.  The  baby  frets,  is  constipated  and  often  has  edema,  con- 
siderable enlargement  of  the  heart  and  cyanosis.  The  blood  pressure  is 
low,  the  liver  enlarged  and  the  pulse  rapid  and  irregular.  This  form  of 
the  disease  occurs  chiefly  in  breast-fed  infants  whose  mothers  have  a 
highly  deficient  diet.  Unless  they  are  treated  promptly,  death  occurs 
within  a  day  or  so. 


Vol.  1.  948 


VITAMIN  Bi:  DIAGNOSIS  452(75) 

Diagnosis 

Until  a  simple,  specific,  laboratory  test  becomes  available,  a  tentative 
diagnosis  must  depend  upon  tiie  interpretation  of  a  reliable  medical  and 
dietary  history  and  a  careful  physical  examination.  It  is  helpful  to  the 
physician  to  bear  in  mind  that  vitamin  Bi  deficiency  occurs  chiefly 
among  the  following  groups: 

1.  The  indigent  and  persons  who  have  erroneous  dietary  habits  and 
idiosyncrasies.  Such  persons  often  subsist  on  a  diet  relatively 
abundant  in  overmilled  rice,  wheat  or  corn.  Their  diets  rarely 
contain  lean  meat,  eggs,  milk,  fish,  fresh  fruits  or  vegetables  in 
sufficient  amounts. 

2.  Persons  who  have  any  organic  disease  that  may  interfere  with  the 
ingestion  or  absorption  of  an  adequate  diet,  the  deficiency  or 
metabolic  diseases  such  as  pellagra,  pernicious  anemia,  sprue, 
alcoholic  neuritis,  Korsakoff's  psychosis,  diabetes  and  myxedema. 
Vitamin  Bi  deficiency  frequently  is  found  in  association  with 
pregnancy  and  lactation,  hunger  edema,  chronic  colitis  and  ca- 
chexia from  any  cause.  Thiamine  deficiency  also  is  found  fre- 
quently in  association  with  diarrhea  from  any  cause.  There  is 
great  danger  of  the  physician's  not  recognizing  isolated  cases  as 
true  thiamine  deficiency. 

3.  Persons  in  whom  the  vitamin  Bi  requirement  is  distinctly  above 
the  average  because  of  growth,  pregnancy  and  lactation,  hard 
physical  exertion,  hyperthyroidism  and  fevers. 

A  diagnosis  of  uncomplicated  thiamine  deficiency  can  be  made  by 
excluding  all  other  causes  of  peripheral  neuritis,  organic  heart  disease, 
edema  and  psycho-neurosis.  The  mild  case  is  much  more  common  than 
acute  case,  but  it  may  be  recognized  only  with  difficulty.  Keeping  in 
mind  the  following  points  noted  by  Vedder^^*^  is  helpful  in  making  an 
early  diagnosis  of  the  disease: 

1.  Slight  pressure  over  the  muscles  of  the  calf  causes  pain. 

2.  Patients  with  beriberi  often  have  areas  of  anesthesia  over  the  ante- 
rior surface  of  the  tibia. 

3.  Any  modification  of  the  patellar  reflexes  is  suspicious. 

4.  If  a  patient  with  beriberi  squats  upon  his  heels  after  the  Oriental 
manner  of  sitting,  he  may  experience  pain  and  inability  to  rise 
without  using  his  hands. 

In  making  a  diagnosis  of  cardiovascular  disturbances  due  to  thiamine 
deficiency  the  big  problem  is  to  rule  out  heart  disease  of  another  etiol- 
VOL.  I.  948 


452(76)  VITAMINS  AND  VITAMIN  DEFICIENCY 

ogy.  The  studies  at  the  University  of  Cincinnati  should  be  very  helpful 
in  this  respect.  Blankenhorn,  Vilter,  Scheinker  and  Austin'''  have 
pointed  out  that  the  cHnical  picture  of  the  faihng  heart  with  exceedingly 
rapid  circulation  is  not  likely  to  be  overlooked,  and  such  cases  are  more 
readily  remembered  than  the  less  dramatic  cases.  The  first  thought  of 
thiamine  deficiency  in  this  type  of  heart  disease  is  when  the  physician 
realizes  that  the  etiological  nature  of  the  heart  condition  is  obscure.  The 
elimination  of  coronary  arteriosclerosis  as  a  cause  is  difficult.  If  the  pa- 
tient has  no  angina  or  precordial  oppression,  no  fever,  no  leukocytosis, 
one  is  a  little  less  likely  to  think  of  coronary  disease  or  Fieldler's  isolated 
myocarditis.  Since  Williams,  Mason  and  Smith'^^  and  \Mlliams,  Mason 
Power  and  Wilder'''^  after  inducing  thiamine  deficiency  in  man,  suggest 
that  three  months  is  about  the  development  time  of  thiamine  deficiency, 
Blankenhorn  and  his  associates  arbitrarily  selected  that  point  to  aid  in  the 
evaluation  of  the  clinical  problem.  Williams,  Mason  and  Smith  observed 
electrocardiographic  changes  which  they  induced  in  subjects  on  thia- 
mine deficient  diets  and  abolished  by  thiamine  administration.  Physicians 
in  the  field  of  nutrition,  however,  find  that  the  electrocardiographic 
findings  are  non-specific,  although  they  may  aid  in  the  final  diagnosis. 
Heart  disease  caused  by  thiamine  deficiency  is  uncommon  in  Amer- 
ica, but  it  does  occur,  and  it  is  curable.  The  first  suggestion  that  the 
heart  disease  may  be  the  result  of  a  deficiency  of  thiamine  may  come 
from  one  of  a  number  of  sources,  and  the  value  of  correlating  the  in- 
formation obtained  by  the  physician,  the  roentgenologist  and  the  nutri- 
tionist cannot  be  overstressed.  The  vivid  description  by  Wenckenbach'"" 
of  the  acute  pernicious  type  of  heart  failure,  which  is  a  valuable  aid  in 
making  a  diagnosis,  may  be  summarized  as  follows: 

1.  Enlargement  of  the  heart  by  percussion,  auscultation  and  x-ray 
examination. 

2.  The  presence  of  murmurs,  chiefly  systolic  but  also  presystolic 

with  a  resonant  first  sound.   The  mumiurs  are  increased  dispro- 
portionately by  exercise. 

3.  Visible  and  palpable  throbbing  pulsations  over  the  heart,  best 

felt  just  to  the  left  of  the  sternum. 

4.  Bounding  pulse  and  thrill  over  the  great  arteries. 

5.  Over-distended  neck  and  ami  veins  and  without  exception  a  pain- 

ful, swollen  liver.  In  the  most  severe  cases,  liver  pulsation. 

A  patient  with  the  more  common  type  of  heart  failure  due  to  vitamin 
Bi  deficiency  resembles  any  other  case  with  degenerative  heart  disease. 
Usually,  however,  it  is  associated  with  edema  and  serous  effusions. 

Vol.  I.  948 


VITAMIN  Bi:  PREVENTION  AND  TREATMENT    452(77) 

Prevention  and  Treatment 

The  Council  on  Foods  and  Nutrition  of  the  National  Research 
Council  has  made  recommendations  in  regard  to  man's  requirements  for 
rhc  various  dietary  factors  necessary  for  normal  physiological  function. 
In  the  chapter  on  riboflavin  the  table  of  the  allowances  for  the  various 
vitamins,  including  vitamin  Bi,  is  shown.  Beriberi  and  subclinical  thia- 
mine deficiency  can  be  decreased  greatly  by  the  application  of  the  fol- 
lowing principles  which  will  go  far  toward  supplying  these  recom- 
mended allowances: 

1.  Fresh  foods  such  as  potatoes,  native  vegetables,  pork,  liver,  eggs, 
milk,  fruits,  beans  and  whole  grain  cereals  should  be  included  in 
the  diet  whenever  possible. 

2.  Since  vitamin  Bi  is  water-soluble,  a  large  amount  of  it  is  lost,  when 
water,  in  which  foods  are  cooked,  is  thrown  away.  It  is  recom- 
mended that  the  water,  in  which  foods  are  cooked,  be  used  for 
broths  and  gravies.  Whole  grain,  barley  or  other  grains,  which  are 
rich  in  thiamine,  may  be  added  to  broths  to  afford  additional 
protection. 

3.  The  use  of  undermilled  or  enriched  flour,  cereals  and  cereal  prod- 
ucts is  the  greatest  single  improvement  that  can  be  made  in  the 
diet  of  the  average  person  in  respect  to  his  thiamine  intake,  and 
their  use  should  be  universal.  This  is  true  particularly  in  low 
cost  diets  in  which  a  preponderance  of  cereal  foods  is  included 
necessarily  because  of  their  relatively  low  cost. 

4.  Persons  chronically  addicted  to  alcohol  and  persons  with  sprue, 
pellagra,  pernicious  anemia,  colitis,  diabetes  mellitus,  tuberculosis, 
senility,  malignancy,  cirrhosis  and  many  other  diseases  are  prone 
to  develop  thiamine  deficiency.  The  incidence  is  high  in  persons 
with  chronic  debilitating  diseases  and  increased  metabolism.  Ac- 
cordingly, particular  attention  should  be  directed  toward  making 
the  diet  of  such  persons  adequate. 

5.  The  diets  of  pregnant  and  lactating  women  should  be  especially 
rich  in  vitamin  Bi.  Whenever  there  is  any  doubt  as  to  the  ade- 
quacy or  utilization  of  food  either  in  the  mother  or  in  the  child, 
supplements  should  be  given.  The  supplements  should  be  con- 
tinued until  the  proper  diet  is  assured.  The  nursing  mother  should 
receive  at  least  5  mgm.  of  thiamine  or  its  equivalent  daily;  the 
infant  should  receive  0.5  mgm.  or  its  equivalent  daily. 

Vol.  I.  948 


452 (7H)  VITAMINS  AND  VllAMIN  DEFICIENCY 

6.    In  persons  with  fever,  severe  gastrointestinal  symptoms,  hyper- 
thyroidism and  other  conditions  the  requirement  for  vitamin  Bi 
may  be  distinctly  above  the  average.   It  is  essential  for  the  physi- 
cian to  prescribe  amounts  above  the  average  for  such  persons.  For 
such  a  maintenance  dose  the  authors  suggest  5  mgm.  to  10  mgm.  of 
S)^nthetic  thiamine  daily  or  its  equivalent  except  when  the  patient 
is  unable  to  absorb  from  the  gastrointestinal  tract.  In  such  instances 
it  is  essential  that  vitamin  Bi  be  given  parenterally  in  order  to  pro- 
tect the  person  from  a  deficiency  of  this  vitamin. 
In  the  treatment  of  thiamine  deficiency  the  problem  is  simply  one 
of  administering  adequate  amounts  of  thiamine  in  the  way  in  which  it 
can  be  utilized.    In  the  adult  and  infant  the  physician  should  direct 
therapy  along  three  lines: 

1.  There  should  be  elimination  of  conditions  causing  excessive  re- 
quirement for  vitamin  Bi  whenever  possible. 

2.  Synthetic  thiamine  or  its  equivalent  should  be  administered  in 
amounts  sufficient  to  correct  the  deficiency. 

3.  There  should  be  symptomatic  treatment  and  treatment  for  co- 
existing diseases. 

The  essence  of  successful  treatment  lies  in  the  administration  of 
adequate  amounts  of  foods  rich  in  thiamine,  supplemented  with  large 
amounts  of  a  specific  therapeutic  agent.  The  diet  should  contain  liberal 
amounts  of  liver,  pork,  lean  meats,  eggs,  whole  grain  or  enriched  bread 
and  cereals,  beans,  peas  and  native  vegetables  and  fruits.  It  should  be 
supplemented  with  the  following  curative  therapeutic  substances;  6 
ounces  of  dried  brewers'  yeast  daily,  6  ounces  of  wheat  germ  daily  or 
10  mgm.  of  synthetic  thiamine  twice  daily.  In  cases  of  severe  thiamine 
deficiency  even  larger  doses  of  synthetic  thiamine  may  be  indicated.  In 
such  cases  it  seems  wise  to  administer  10  to  20  mgm.  twice  daily  until 
the  signs  of  thiamine  deficiency  have  disappeared.  In  cases  of  mild  defi- 
ciency doses  of  10  mgm.  daily  are  adequate.  There  is  no  question,  but 
that  the  oral  administration  of  thiamine  in  adequate  doses  is  efficacious 
in  the  average  case.  Parenteral  administration  of  2  5  mgm.  twice  daily  is 
recommended,  however,  when  the  deficiency  is  associated  with  severe 
cardiac  failure,  severe  peripheral  neuritis  or  severe  gastrointestinal  dis- 
turbances, or  when  the  patient  is  refractory  to  oral  therapy. 

Infantile  thiamine  deficiency  is  treated  most  satisfactorily  by  giving 
intramuscularly  or  intravenously  5  to  10  mgm.  of  thiamine  in  sterile 
physiological  solution  of  sodium  chloride  twice  daily.  As  in  the  adult  the 
action  is  more  prompt  and  more  efficacious,  when  it  is  administered 

Vol.  I.  948 


VITAMIN  Bi:  TOXICITY  452(79) 

parenterally  than  when  it  is  given  by  mouth.  When  injections  cannot 
be  (riven  conveniently,  or  when  the  infant  is  convalescent,  10  mgm.  of 
chrystalline  vitamine  Bi  may  be  given  orally  every  day.  Obviously,  sat- 
isfactory treatment  of  the  n'lother  will  aid  greatly  in  the  treatment  of  the 
nursing  child. 

loxiciTV 

The  practicing  physician  should  have  in  mind  that  there  is  a  great 
difference  between  the  therapeutic  and  the  toxic  dose  of  thiamine.  The 
authors,  who  have  been  studying  this  vitamin  for  ten  years,  have  seen 
no  evidence  of  cumulative  toxicity  in  human  beings.  We  have  given  as 
much  as  500  mgm.  daily  to  patients  for  a  period  of  sixty  days  without 
any  evidence  of  toxic  effects.  Since  the  therapeutic  dose  in  man  is  only 
a  few  milligrams  a  day,  we  consider  it  a  remarkably  safe  therapeutic 
agent.  \\g  have  reported  that  large  amounts  of  synthetic  crystalline 
material,  when  injected  intravenously,  frequently  cause  the  patient  to 
volunteer  that  he  experiences  a  yeast-like  taste.  There  is  no  doubt  that 
some  persons  have  an  indiosyncrasy  to  this  substance,  just  as  they  may 
have  other  drug  idiosyncrasies,  and  patients  may  become  hypersensitive 
in  the  course  of  treatment. 


Vol.  I.  948 


452 (Ho)  VITAMINS  AND  VITAMIN  DEFICIENCY 

NICOTINIC  ACID  AMIDE 

History 

Nicotinic  acid  Mas  first  prepared  from  nicotine  by  Huber  in  1867^", 
but  its  significance  in  nutrition  was  not  discovered  for  many  years. 
Between  191 2  and  19 16  it  was  isolated  from  rice  poiishings  by  Susuke, 
Shimamuri  and  Odake""",  Funk""'  and  Williams^"^'"'  and  in  1926 
\^ickery"°'^  found  it  in  yeast.  The  amide  of  nicotinic  acid  was  shown  to 
be  the  active  group  of  the  coenzyme  now  known  as  coenzyme  II  by 
Warburg  and  Christian""'  in  1935,  and  at  the  same  time  Kuhn  and  Vet- 
ter""^  isolated  it  from  the  red  blood  cells  of  the  horse  and  from  mamma- 

H 

C  O 

HC  C  —  C 

I  \ 

HC  CH  OH 

I'ig-  33-     Structural  formula  of  nicotinic  acid   (3-pyridine  carbolic  acid.) 

lian  heart  muscle.  As  a  result  of  this  work  the  interest  of  many  investi- 
gators was  directed  toward  discovering  the  role  of  nicotinic  acid  in 
nutrition.  In  1937  Elvehjem,  Madden,  Strong  and  Wooley-"^  isolated  it 
from  liver  and  showed  that  it  was  curative  in  canine  blacktongue.  Inde- 
pendently and  almost  simultaneously  excellent  results  in  treating  human 
pellagra  were  reported  by  several  investigators'"^ 


,.210,211.212,213 


Chemistry  and  Physiology 

There  are  several  ways  of  preparing  nicotinic  acid,  one  of  which  is 
the  strong  acid  oxidation  of  nicotine.  It  was  from  this  method  of  prepa- 
ration that  nicotinic  acid  received  its  name.  The  formula  for  nicotinic 
acid  is  shown  in  Fig.  33,  that  for  its  amide  in  Fig.  34.  Its  properties,  how- 
ever, differ  widely  from  the  parent  compound.  Nicotinic  acid,  the  beta- 
carboxylic  acid  of  pyridine,  is  a  white  crystalline  compound  (Fig.  35) 
Vol.  I.  948 


NICOTINIC  ACID  AiMIDE:  CHEMISTRY 


452^«0 


which  mehs  at  230  to  232°  C.  It  is  moderately  soluble  in  hot  water  but 
only  slightly  soluble  in  cold  water.  The  sodium  salt  and  the  amide  are 
more  soluble.  For  parenteral  administration  the  amide  is  preferable 
because  it  does  not  cause  the  flushing  produced  by  nicotinic  acid. 

Nicotinic  acid  is  very  stable  and  is  not  oxidized  or  destroyed  by 
ordinary  cooking  processes  or  by  exposure  to  light. 


H-C 


^ 


C 


H-C 


% 


N 


C-C 


.^' 


\ 


NH 


C-H 


Nicotinic  Acid    Amide 

3-pLjridine    carboxi^lic    acid    arnide 

Fig.  ^4.     Structural  formula  of  nicotinic  acid  amide. 

It  is  widely  distributed  in  foodstuffs,  but  even  the  richest  sources, 
such  as  liver,  eggs,  salmon,  and  whole  cereals,  contain  relatively  little  of 
this  substance. 

Rehniovsbip  hetiveeii  Co-enzymes  I  mid  II 
iTJJii  Nicotinic  Acid  Amide  Deficiency 

The  spectacular  clinical  improvement,  which  follows  the  administra- 
tion of  nicotinic  acid  or  nicotinic  acid  amide  to  pellagrins,  led  to 
increased  interest  in  the  respiratory  co-enzymes  I  and  II,  cozymase  and 
coferment,  respectively,  which  are  known  to  contain  nicotinic  acid 
amide.  By  definition  these  co-enzymes  are  relatively  heat-stable,  dialysa- 
ble,  organic  catalysts  which  retain  activity  even  when  separated  from  the 
living  cell.    They  are  necessary  for  the  function  of  specific  protein 

Vol.  I.  948 


452(82)  VITAMINS  AND  VITAMIN  DEFICIENCY 

enzymes.  Each  is  produced  by  living  cells  from  a  combination  of  nico- 
tinic acid  amide,  ribose,  adenylic  acid  and  phosphoric  acid.  The  present 
knowledge  of  the  chemical  constitution  of  co-enzymes  I  and  II  indicates 
that  they  are  similar  in  that  both  are  pyridine  nucleotides,  differing  only 
in  their  content  of  phosph(;ric  acid.  The  authors  of  this  chapter  consider 
that  the  formation  of  enzymes  governing  respiration  and  growth  of  cells 
involves  the  synthesis  of  complex  substances  from  simple  compounds. 


Fig.  35.    Crystalline   nicotinic   acid    (courtesy  of   Merck   and   Co.). 

The  methods  for  studying  the  enzymes  are  tedious  and  are  not 
recommended  for  the  practicing  physician.  Nevertheless  they  offer  im- 
portant infomiation  concerning  certain  aspects  of  the  pathogenesis  of 
pellagra  and  other  diseases.  \^ilter,  A^ilter  and  Spies"^*  found  that  the 
concentration  of  co-enzymes  I  and  II  in  the  whole  blood  of  persons  with 
deficiency  diseases  is  slightly  lower  than  in  normal  persons  on  optimal 
diets.  Low  values  for  the  co-enzyme  concentration  of  whole  blood  may 
be  observed  also  in  some  persons  with  diabetes  mellitus,  roentgen  sick- 
ness, leukemia  and  pneumococcal  pneumonia.  Infections,  fever  and 
excessive  physical  exercise  tend  to  lower  the  concentration  in  the  blood, 
whereas  rest  in  bed  and  an  increased  intake  of  nicotinic  acid  or  related 
pyridine  compounds  tend  to  increase  the  concentration. 

Axelrod,  Spies  and  Elvehjem"^^  studied  a  large  series  of  pellagrins 
admitted  to  the  Nutrition  Clinic  at  the  Hillman  Hospital  in  Birmingham, 
Alabama.  Using  a  yeast  growth  method,  which  is  specific  for  co-enzyme 
I,  they  found  that  there  was  only  a  slight  lowering  of  this  substance  in 
the  erythrocytes.  There  was  a  great  decrease  in  the  co-enzyme  content 
of  the  striated  muscle,  and  it  continued  to  decrease  as  the  pellagra  became 
more  severe,  whereas  it  increased  following  the  administration  of  nico- 
tinic acid  or  nicotinic  acid  amide.  It  should  be  emphasized  that  in  these 
Vol.  I.  948 


NICOTINIC  ACID  AMIDE:  CHEAIISTRY  452(83) 

studies  a  method  specific  for  co-enzyme  I  was  used,  and  it  had  no  bearing 
on  the  co-enzyme  II  content  of  the  tissues.  The  precise  significance  of 
this  lowering  in  the  co-enzyme  I  content  of  the  pellagrin's  muscles  can- 
not be  fully  stated.  Unpublished  observations  by  Lu  and  Spies-'''  indicate 
that  the  changes  in  the  oxidative  metabolism  of  the  striated  muscle  taken 
from  the  pellagrin  are  less  than  those  found  in  nomial  controls.  These 
investigators  observed  that,  following  therapy,  normal  values  in  the 
muscles  of  pellagrins  soon  were  restored.  The  anti-pellagric  value  of  a 
substance,  however,  is  not  necessarily  associated  with  its  ability  to  affect 
the  co-enzyme  I  content  of  the  blood  and  other  tissues.  For  example 
nicotinic  acid  has  a  profound  effect  upon  the  co-enzyme  I  content  of 
human  blood  both  in  vivo  and  in  vitro,  while  coramine,  the  diethylamide 
of  nicotinic  acid,  which  is  also  anti-pellagric,  does  not  produce  a  signifi- 
cant increase  in  the  co-enzyme  I  content  of  erythrocytes  and  muscles. 
The  fact  that  the  very  ill  pellagrin  may  have  only  60  per  cent,  of  the 
normal  concentration  of  co-enzyme  I  in  his  muscles  offers  a  marvelous 
explanation  of  the  long,  lingering  weakness  which  characterizes  the 
period  of  development  of  dietary  deficiency  disease.  Spies,  von  Euler, 
Vilter,  Bean  and  Schlenk  in  unpublished  observations  have  shown  that 
the  intravenous  injection  of  from  10  to  50  mgm.  of  co-enzyme  I  of  the 
highest  activity  is  followed  by  dramatic  clinical  improvement  in  the 
acute  manifestations  of  pellagra;  yet,  this  amount,  when  distributed 
throughout  the  body,  is  not  detectable  by  their  highly  sensitive  labora- 
tory methods. 

Absorption,  Distribution,  Excretion  and  Effects 

Unpublished  observations  by  Bean,  Dexter  and  Spies  showed  that 
nicotinic  acid  is  absorbed  from  the  stomach  and  from  the  small  and 
large  bowel.  Absorption  is  more  rapid  from  an  empty  stomach  than  it  is 
after  meals.  If  the  absorption  is  sufficienty  rapid,  the  concentration  of 
nicotinic  acid  is  increased  in  the  blood,  and  the  skin  temperature  of 
the  upper  part  of  the  body  is  elevated.  Over  80  per  cent,  of  the  persons 
to  whom  100  to  300  mgm.  of  nicotinic  acid  is  administered  orally  feel 
temporary  prickly  or  burning  sensations  of  the  skin.  A  few  persons 
complain  of  nausea  and  cramping  pains  in  the  stomach.  These  symptoms 
are  transitory  and  are  not  associated  with  changes  in  general  body 
temperature,  pulse,  respiration  or  blood  pressure.  All  persons  to  whom 
20  mgm.  of  nicotinic  acid  is  administered  rapidly  by  the  intravenous 
route  have  transitory  vasodilation.   It  should  be  remembered,  however, 

Vol.  I.  948 


452(84) 


VITAMINS  AND  VITAMIN  DEFICIENCY 


that  nicotinic  acid  amide  is  the  more  physiological  form  of  the  com- 
pound, and  it  does  not  produce-  these  vasodilating  reactions.  There  is 
some  tendency  for  the  blood  vessels  of  the  lower  extremities  to  constrict 
following  the  administration  of  nicotinic  acid,  and  the  amounts  and 
methods  of  administration  have  a  profound  effect  on  the  skin  tem- 
perature rise  as  is  shown  in  Fig.  36. 

5KIN  TEMPERATURE  RISE  AFTER  NICOTINIC  ACID 


RI5E  IN  TEMP 


AMOUNTS   AND  METHODS- 
OF  ADMINISTRATION 


20  m^.  I.V. 

100  m6  oral  I L)  after 
meal 


100  m§  orally  alter 
jasTi'n^  (3  hrs. 
100  m§.  orally  after 
50  mo  Clucine 
5        10       15       20     25       JO  ^    ^  ^ 

TIME  IN    MINUTES    AFTER    ADMINISTRATION 
OF   NICOTINIC  ACID 


Fig.  36.     Skin  temperature  rise  after  nicotinic  acid   (from  Duncan  Graham:   Disease 
of  Aletabolism,  AA'.  B.  Saunders  Co.,  Phila.,  194:). 


Nicotinic  acid  amide  and  co-enzymes  I  and  II  are  present  in  the 
blood  and  are  excreted  in  the  urine.  These  substances  are  so  essential 
that  the  body  does  not  allow  the  blood  levels  to  be  lowered  greatly. 
The  amount  excreted  in  the  urine  is  dependent  upon  many  factors, 
including  the  richness  of  the  diet  and  the  concentration  in  the  body 
tissues.  When  they  are  administered  in  pure  form,  the  amount  excreted 
depends  on  the  size  of  the  dose  and  the  mode  of  administration.  Excre- 
tion is  more  rapid  when  the  material  is  administered  parenterally  than 
when  it  is  given  orally.  AMien  large  doses  of  nicotinamide  are  injected 
into  human  beings,  the  material  cannot  be  accounted  for  eitlicr  un- 
changed or  as  known  derivatives  in  the  urine.  Even  after  repeated  doses 
large  amounts  do  not  appear  in  the  urine  and,  therefore,  must  be 
metabolized  in  ways  at  present  unknown.  The  metabolic  derivative  of 
nicotinamide  is  N-methyl-nicotinamide.  Even  after  repeated  injections 
of  this  substance  it  does  not,  for  the  most  part,  appear  in  the  urine.  It 
should  be  emphasized  that  for  a  long  time  it  was  taken  for  granted  that 
human  beings  excreted  trigonelline,  the  methvl  betaine  of  nicotinic 
acid,  as  do  dogs.    It  is  known  now  that  N-methyl-nicotinamide  is  the 

Vol.  1.  948 


NICOTINIC  ACID  AMIDE:  CHEMISTRY  452(85) 

metabolic  derivative  chiefly  excreted.  The  co-enzymes  I  and  II  increase 
in  the  blood  and  urine  after  nicotinic  acid  is  administered. 

Nicotinic  acid  compounds  have  been  found  in  nearly  all  animal 
tissue.  In  general  the  concentration  is  highest  in  tissues  in  which  the 
metabolism  is  high.  In  human  beings  with  severe  nicotinic  acid  defici- 
ency, the  concentration  of  the  nicotinic-acid-amide-containing  substance, 
co-enzyme  I,  is  decreased  as  much  as  60  per  cent,  in  striated  muscle  and 
may  be  slightly  decreased  in  the  erythrocytes.  Likewise  in  this  de- 
ficiency the  content  of  the  nicotinic  acid  derivatives  is  below  normal 
in  whole  blood  and  urine.  When  such  patients  are  treated  with  nico- 
tinic acid,  the  content  of  the  compounds  in  the  muscle,  blood  and  urine 
containing  nicotinic-acid-amide  increases. 

A  knowledge  of  the  level  of  nicotinic  acid  in  the  body  tissues  and 
excretions  of  pellagrins  sometimes  contributes  valuable  information 
concerning  the  degree  of  nicotinic  acid  deficiency.  It  also  is  useful  in 
following  the  rate  of  recovery  after  nicotinic  acid  therapy  has  been 
initiated.  Several  methods,  both  chemical  and  microbiological,  for  the 
determination  of  nicotinic  acid  in  micro  quantities  have  been  introduced. 
In  studying  biologically  derived  specimens  we  use  the  microbiological 
technics  because  they  possess  extreme  sensitivity,  permitting^  the  deter- 
mination of  nicotinic  acid  in  amounts  as  small  as  a  few  hundredths  of  a 
microgram  and  may  be  used  in  analyzing  for  nicotinic  acid  in  the  pres- 
ence of  large  amounts  of  foreign  material  even  if  this  be  pigmented  or 
in  a  solid  state.  The  microbiological  method  of  Snell  and  AVrig^ht  has 
been  used  successfully  in  determining  minute  quantities  of  nicotinic 
acid  in  blood,  urine,  feces,  saliva,  fresh  tissues  and  foods.  Using  this 
method.  Gross,  Swain  and  Spies'"  have  found  .that  the  average  person 
with  pellagra  retains  more  of  a  100  mgm.  test  dose  of  nicotinic  acid  than 
does  the  normal  person  of  similar  size. 

Figment  Metabolism 

In  191 3  iMyers  and  Fine  observed  that  indicanuria  was  pronounced 
in  pellagrins  in  the  presence  of  low  hydrochloric  acid  in  the  gastric 
contents.  Three  years  later  Hunter  showed  that  the  previous  diet  was 
important  in  the  determination  of  the  fate  of  additional  ingested  trypto- 
phane and  reported  the  finding  of  urorosein  in  the  urine  of  pellaq-rins. 
Studies  by  the  authors  show  that  many  pellagrins  excrete  indole,  indican, 
urorosein  and  various  other  related  compounds  in  the  urine.  A  number 
of  investigators  have  found  porphyrin  in  the  urine  of  pellagrins.  At  one 

Vol.  I.  948 


452(86)  VITAAIINS  AND  VITAMIN  DEFICIENCY 

time  it  was  thought  that  the  excretion  of  porphyrin  might  be  useful  as  a 
diagnostic  test.  It  now  appears  that  porphyrinuria  is  a  resuh  of  hver 
damage  or  at  least  a  disturbance  of  liver  function.  Naturally  the  alco- 
holic pellagrin  is  more  prone  to  have  liver  disease  than  the  endemic 
pellagrin.  Urorosein  and  indican  frequently  are  excreted  in  large 
amounts  in  early  or  subclinical  pellagra,  so  that  their  detection  may  serve 
as  a  valuable  warning  signal  of  malnutrition.  The  test  using  colorimetric 
methods  is  a  simple  but  non-specific  one.   The  procedure  is  as  follows: 

A  measured  amount  of  urine  (3  to  10  c.c.)  is  acidified  with  glacial 
acetic  acid  to  a  pH  of  about  4.0  and  shaken  with  5  to  20  c.c.  of  ether  until 
no  more  red  pigments  can  be  extracted.  The  ether  then  is  washed 
repeatedly  with  water.  A  complete  separation  of  the  two  layers  is 
allowed  to  take  place.  To  a  measured  fraction  of  the  ether  is  added 
one-fifth  of  that  amount  of  25  per  cent,  hydrochloric  acid.  On  shaking 
the  pigments  contained  in  the  ether  fraction  are  transferred  completely 
to  the  hydrochloric  acid,  which  becomes  stained  purple  or  pink,  the 
intensity  of  the  color  depending  on  the  pigment  concentration.  The 
colorimetric  estimation  is  made  either  in  a  colorimeter  of  Dubosq  type 
against  a  standard  solution  of  porphyrin  or  by  comparison  with  por- 
phyrin solutions  of  known  concentration.  The  time  necessary  for  the 
complete  transfer  of  the  porphyrins  from  the  urine  into  the  ether  and 
from  the  ether  into  hydrochloric  acid  differs  in  various  specimens,  being 
determined  by  the  nature  of  the  substance  present.  In  most  specimens 
the  process  is  completed  in  a  half  an  hour,  but  as  a  check  the  colorimetric 
estimations  may  be  repeated  after  three  hours  and  after  twenty-four 
hours. 

Severe  cases  may  have  a  negative  test. 

Pathological  Physiology 

The  most  common  gross  pathological  findings  of  nicotinic  acid  defi- 
ciency are  generalized  emaciation  of  the  body  and  atrophy  of  various 
organs.  In  some  cases  the  walls  of  the  gastrointestinal  tract  may  show 
swelling,  reddening  and  ulceration  of  any  portion,  while  in  other  cases 
the  walls  may  be  thin  and  atrophic.  The  liver  occasionally  contains 
abnormal  amounts  of  fat.  Moore,  Spies  and  Cooper ^^  made  a  histologic 
study  of  the  active  lesions  and  also  of  clinically  unaffected  areas  of  the 
skin  in  the  same  patient. 

The  microscopic  picture  of  the  lesions  of  pellagra  is  similar  to  that 
found  in  chronic  inflammatory  diseases  of  the  skin.  The  skin  from  both 

Vol.  I.  948 


NICOTINIC  ACID  AMIDE:  SYMPTOMATOLOGY    452(87) 

clinically  affected  and  unaffected  areas  in  pellagrins  was  hyperkeratotic. 
Parakeratosis  was  found  also  in  the  actual  lesions.  No  satisfactory 
explanation  of  the  atrophy  which  is  present  both  in  healing  pellagrous 
lesions  and  in  the  unaffected  skin  can  be  given.  That  atrophy  occurs 
normally  with  aging  of  the  skin  and  that  it  may  result  from  either 
external  or  internal  pressure  has  long  been  known,  but  the  exact 
mechanism  involved  in  the  process  remains  unexplained,  and  the  present 
study  affords  no  new  information  concerning  it.  Both  the  affected  and 
unaffected  skin  showed  edema  of  the  corium  and  a  moderate  infiltration 
of  lymphocytes.  Since  the  skin  lesions  tend  to  disappear  following 
treatment  with  nicotinic  acid,  they  are  to  a  considerable  extent  reversible, 
so  it  seems  that  they  represent  a  specific  response  on  the  part  of  the  skin 
to  a  deficiency  of  nicotinic  acid  and  substances  that  act  similarly.  The 
microscopic  picture  of  the  intestinal  lesions  varies  from  atrophy  to  acute 
intiammation  characterized  by  fibrin  formation  and  collections  of  inflam- 
matory cells.  When  changes  in  the  nervous  system  are  demonstrable, 
they  are  characterized  by  irregular  areas  of  degeneration,  often  involv- 
ing the  posterior  and  lateral  columns  of  the  spinal  cord,  the  posterior 
spinal  ganglia,  and  the  Betz  and  Purkinje  cells. 


Symptoaiatology 

As  is  shown  in  Fig.  37,  there  is  a  lag  period  between  the  onset  of 
symptoms  and  the  time  the  patient  seeks  medical  aid.  The  time  between 
the  very  first  day  of  dietary  deficiency  and  the  appearance  of  lesions 
might  well  be  termed  the  deficiency  development  time.  This  period 
of  time  may  be  of  long  duration  with  insidiously  advancing  symptoms, 
trivial  in  nature  but  gaining  importance  by  their  persistency  rather  than 
by  their  severity.  Before  diagnostic  lesions  of  the  mucous  membranes 
or  skin  appear,  there  is  loss  of  appetite  which  is,  at  least  in  part,  re- 
sponsible for  weight  loss.  Ill-defined  disturbances  of  the  alimentary 
tract  including  "indigestion"  and  changes  in  bowel  function  occur. 
General  muscular  weakness,  lassitude,  irritability,  depression,  memory 
loss,  headache  and  insomnia  frequently  develop  without  apparent  reason. 
Abdominal  pain,  burning  sensations  in  various  parts  of  the  body,  vertigo, 
numbness,  nervousness,  palpitation,  distractability,  flights  of  ideas,  appre- 
hension, morbid  fears,  mental  confusion  and  forgetfulness  frequently 
occur.  There  may  be  intermittent  diarrhea  and  constipation.  There  is 
much  that  obviously  is  abnormal  at  this  stage  but  nothing  that  is  pathog- 
VOL.  I.  948 


452(88) 


VITAAIINS  AND  VITAA1IN  DEFICIENCY 


nomonic.  Since  the  entire  syndrome  often  appears  without  objective 
cause,  a  diagnosis  of  neurasthenia,  anxiety  state,  mahngering  or  neurosis 
may  be  entertained  by  the  physician.   These  symptoms  are  not  invari- 


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ONser  OF  SYMPTOMS 

FIBST      VISIT     TO    CLINIC 


Fig.  37.     Lag  period  between  onset  of  symptoms  and  first  visit  to  clinic. 

ably  present;  they  do  not  appear  in  any  regular  order,  and  they  are  not 
uniformly  severe  in  every  case.  The  individual  case,  however,  usually 
repeats  the  same  order  of  development  of  symptoms  with  each  recur- 
rence. 

Although  the  identity  of  pellagra  in  children  and  adults  is  established, 
the  clinical  manifestations  often  are  different,  and  for  purposes  of  clarity 
it  is  advisable  to  consider  them  separately.  It  should  be  borne  in  mind, 
however,  that  from  an  etiological  and  pathological  point  of  view  such  a 
distinction  is  artificial. 

Endemic  pellagra  in  infants  and  children  has  been  reported  by  Spies, 
Walker  and  Woods'-^".  These  investigators  find  that  a  careful  dietary 
history  of  the  mother  usually  reveals  that  her  diet  has  been  inadequate 
during  pregnancy  and  lactation.  Frequently  her  milk  supply  is  scanty, 
and  the  infant  is  weaned  soon  after  birth  and  given  food  inadequate  for 
proper  nutrition,  or  the  inadequate  breast  milk  feedings  are  supplemented 
with  such  foods.    From  an  early  age  most  of  the  children  have  poor 

Vol.  1.  948 


NICOTINIC  ACID  AMIDE:  DIAGNOSIS  452(^9) 

appetites  and  eat  irregularly.  As  a  rule,  they  prefer  carbohydrate  foods 
and  often  refuse  all  others.  Usually  they  develop  poor  food  habits  early 
in  life,  and  the  parents  seldom  make  any  attempt  to  change  them,  even  if 
a  good  diet  becomes  available.  The  parents  frequently  complain  that  the 
children  are  irritable,  easily  frightened,  apprehensive,  fretful  and  cry 
a  great  deal;  that  they  are  too  tired  to  play  but  too  nerv^ous  to  rest;  that 
they  sleep  poorly  and  frequently  awaken  crying.  Few  of  them  gain 
weight  normally,  and  the  few,  who  were  robust  prior  to  their  illness, 
usually  have  lost  weight  rapidly.  In  these  children  soreness  of  the  lips 
and  tongue  and  burning  of  the  stomach  are  common  complaints  as  are 
pains  in  the  abdomen,  cramping  of  the  legs  and  cramping  and  burning  of 
the  feet.  Usually  they  are  constipated  but  have  occasional  bouts  of 
diarrhea  during  the  spring  and  summer.  These  symptoms  wax  and  wane 
and  become  more  severe  with  each  recurrence.  As  the  children  grow 
older,  the  subnormality  in  height  and  weight  usually  becomes  more 
apparent  as  does  an  increasing  inability  to  concentrate  or  to  make  normal 
progress  in  school.  From  the  physical  examination  it  is  obvious  that  these 
children  are  in  ill  health.  They  appear  undernourished  and  underde- 
veloped for  their  age.  Usually  their  skin  is  dry  and  atrophic,  makincj 
them  appear  much  older  than  they  are.  The  typical  demial  and  alimen- 
tary tract  lesions  described  in  adult  pellagra  may  or  may  not  develop.  A 
more  complete  discusion  of  pellagra  as  a  disease  will  be  found  in  Chapter 
XIII,  Vol.  IV  of  Oxford  Medicine. 


DlACXOSTS 

The  clinical  diagnosis  of  pellagra  in  adults  or  children  depends  upon 
identifying  typical  dermal  lesions  or  characteristic  mucous  membrane 
lesions  or  both. 

Characteristic  skin  lesions  may  appear  on  any  part  of  the  body. 
They  are  observed  most  frequently  over  sites  of  irritation,  such  as  the 
dorsum  of  the  hands,  wrists,  elbows,  face,  neck,  knees,  feet,  under  the 
breasts  and  in  the  perineal  region.  In  most  instances  the  area  of  dermatitis 
is  separated  sharply  from  the  nomial  skin.  The  lesions  are  never  static; 
they  either  advance  or  regress.  The  dermatitis  begins  as  an  erythema 
resembling  sunburn.  As  the  disease  progresses,  the  area  becomes  reddish 
brown,  roughened,  scaly  and  keratotic;  vesicles  and  bullae  may  form. 
Desquamation  usually  begins  at  the  center  of  the  lesion,  and  the  underly- 
ing skin  appears  red  and  thickened.   The  intensity  of  the  pigmentation 

Vou  I.  948 


452 (9o)  VITAMINS  AND  VIIAMIN  DEFICIENCY 

and  the  thickening  of  the  skin  tend  to  increase  with  each  recurrence  of 
the  disease.  After  repeated  recurrences  the  skin  may  become  either  per- 
manently pigmented,  thick  and  roughened  or  thin  and  atrophic.  In  the 
past  a  diagnosis  of  pellagra  was  not  ventured  unless  well-established 
bilateral  lesions  were  evident.  Such  lesions  are  much  more  common  than 
unilateral  lesions.  Nevertheless,  Bean,  Spies  and  Vilter~-"  found  32  pa- 
tients with  well-advanced  unilateral  pellagrous  dermatitis  in  a  series  of 
889  cases.  These  investigators  emphasize  that  in  their  experience  the 
cutaneous  lesions  in  diiferent  parts  of  the  body  often  are  in  different 
phases  simultaneously.  One  lesion  may  be  at  the  stage  of  early  erythma, 
another  in  the  stage  of  desquamation,  and  still  another  in  the  stage  of 
pigmentation.  Sunlight  as  the  exciting  agent  of  pellagrous  dermatitis 
has  been  discussed  for  years  by  many  investigators.  Some  of  the  series 
of  opinions  have  been  discussed  by  Smith  and  Ruffin--\  Spies""  and 
Stannus"^  Suffice  it  to  say  that  lesions  not  exposed  to  the  sun  occur, 
but  it  is  generally  agreed  that  exposure  to  sunlight  is  more  detrimental  to 
pellagrins  than  it  is  to  normal  persons. 

Glossitis  and  stomatitis  are  early  and  common  symptoms  of  pellagra, 
and  Spies"^  has  demonstrated  that  pellagrous  glossitis  is  a  much  more 
sensitive  gage  than  dermatitis  in  the  evaluation  of  the  severity  of  the 
disease.  In  the  early  stage  of  the  disease  only  the  tip  or  the  lateral  margins 
of  the  tongue  are  swollen  and  reddened.  In  the  absence  of  treatment  the 
swelling  increases,  redness  becomes  more  intense,  and  deeply  penetrating 
ulcers  may  appear  along  the  sides  and  tip  but  rarely  on  top.  The  entire 
surface  may  be  covered  with  a  thick  gray  membrane  filled  with  debris 
and  Vincent's  organisms.  The  tongue  may  be  hypersensitive,  although 
it  usually  is  hypoesthetic.  The  buccal  mucous  membranes,  the  mucocu- 
taneous surface  of  the  lips,  the  gums  and  the  palate  likewise  may  be 
affected.  A  burning  sensation  of  the  tongue  and  of  the  mucous  mem- 
branes of  the  pharynx,  esophagus  and  stomach  is  not  uncommon  and 
usually  is  aggravated  by  hot  or  acid  foods.  Ptyalism  and  nausea  may 
occur  early,  but,  as  a  rule,  they  are  advanced  symptoms  of  the  disease. 
Achlorhydria  is  present  in  about  50  per  cent,  of  persons  with  pellagra, 
even  after  histamine  stimulation;  rennin  and  pepsinogen  likewise  are 
absent.  In  the  majority  of  mild  cases  the  bowels  act  normally  or  are 
constipated.  Severe,  persistent  diarrhea  with  frequent  watery  stools 
tends  to  occur  only  in  the  more  acute  cases.  Abdominal  discomfort,  pain 
and  distention  may  be  present  at  any  time  during  the  course  of  the 
disease  and  usually  are  more  severe  after  a  large  meal. 

Mental  symptoms  as  a  part  of  the  pellagra  syndrome  have  been  em- 

VOL.  I.  948 


NICOTINIC  ACID  AMIDE:  TREATMENT  452  (91 ) 

phasized  for  many  years.  The  patient  may  present  a  train  of  symptoms 
characteristic  of  neurasthenia,  anxiety  state  or  other  neuroses.  In  later 
stages  there  is  loss  of  memory,  excitement,  mania,  delirium,  hallucina- 
tions and  dementia.  Even  in  the  absence  of  diagnostic  lesions  of  pellagra 
the  patient  may  have  central  nervous  system  involvement. 

A  series  of  severe  cases  of  pellagra  u'ith  atypical  lesions  has  been 
described  by  Spies,  Cogswell  and  Vilter"".  This  type  of  case  is  difficult 
to  diagnose  and  is  likely  tcf  be  fatal,  if  proper  therapy  is  not  applied 
promptly. 

A  history  of  prolonged  subsistence  on  a  deficient  diet  plus  the 
presence  of  pellagra  in  other  members  of  the  family  should  lea.d  the 
physician  to  suspect  pellagra  even  in  the  absence  of  typical  pellagrous 
lesions.  When  there  is  any  doubt,  the  controlled  therapeutic  test  should 
be  given,  since  it  is  known  that,  if  early  pellagra  is  present,  rapid  improve- 
ment will  follow  specific  therapy. 


Prevention  and  Treatment 

Like  most  nutritional  deficiency  states  nicotinic  acid  deficiency  is 
particularly  prevalent  among  the  following  groups,  and  it  is  to  these 
groups  that  special  attention  toward  prevention  should  be  directed. 

I.  The  poor  and  ignorant,  who  subsist  on  an  unbalanced  diet, 
usually  rich  in  cereals  and  low  in  meat,  milk  and  eggs.  Casal,  who  first 
described  pellagra,  pointed  out  that  "mal  de  la  rosa"  occurred  among 
people  who  ate  com  for  a  staple  cereal.  Endemic  pellagra  has  occurred 
almost  exclusively  among  people  who  ingest  com  or  com  products.  The 
hypothesis  that  com  plays  a  role  in  the  etiology  of  the  disease  has  com- 
manded continued  attention.  After  finding  that  nicotinic  acid  was  a  use- 
ful therapeutic  agent,  investigators  have  been  much  interested  in  possible 
antag-onism  between  it  and  corn.  Evidence  of  this  antao-onism  has  been 
extended  by  the  observations  of  Krehl,  Sarma,  Teply  and  Elvehjem""^ 
who  showed  that  cornmeal  or  corn  grits  added  to  a  low  protein  diet 
greatly  reduced  the  growth  of  young  rats,  and  that  addition  of  i  mgm. 
of  nicotinic  acid  per  100  grams  of  diet  restored  growth  to  the  level 
observed  when  the  diet  contained  no  corn  products.  These  investigators 
next  learned  that  tryptophane  could  overcome  the  growth  inhibitors 
present  in  the  corn  products.  It  is  of  considerable  dietary  interest  that 
polished  rice  contains  less  nicotinic  acid  than  corn  but  more  tryptophane. 
From  a  clinical  point  of  view  it  is  of  great  interest  that  pellagra  occurs 

Vol.  I.  948 


452(92)  \'ITAMINS  AND  VITAMIN  DEFICIENCY 

in  persons  who  have  never  eaten  maize  (com),  but  most  of  the  endemic 
pellagrins  of  the  world  are  heavy  corn  eaters.  Pellagrins,  who  normally 
have  a  low  level  of  vitamins  in  their  tissues,  would  be  most  susceptible  to 
any  deleterious  action  of  com.  Pellagrous  lesions  heal  spectacularly, 
while  the  patient  is  restricted  to  a  diet  of  com  products,  if  adequate 
amounts  of  nicotinic  acid  are  administered. 

2.  Persons  who  because  of  organic  diseases  have  difficulty  in  ingest- 
ing^, assimilating  or  utilizing  food.  In  this  group  are  included  persons 
whose  diseases  predispose  them  to  pellagra,  which  usually  is  referred  to 
as  pellagra  secondary  to  organic  disease.  More  males  than  females  have 
pellagra  secondary  to  cancer  and  ulcer  of  the  stomach.  In  pellagra  fol- 
lowing measles  and  whooping  cough  children  naturally  predominate. 
Childbearing  and  its  associated  complications  predispose  women  from 
20  to  40  years  of  age  to  pellagra,  if  their  diets  are  of  borderline  adequacy, 
and  the  incidence  is  highest  among  women  in  this  age  group.  Bean,  Spies 
and  Blankenhom--'  have  discussed  the  perilous  burden  which  organic 
disease  and  surgical  operations  place  on  the  undernourished. 

3.  Persons  who  are  chronically  addicted  to  alcohol  and  who  eat 
very  little  food  frequently  develop  pellagra  which  often  is  referred  to  as 
alcoholic  pellagra  or  pseudo-pellagra. 

4.  Food  faddists  and  persons  with  capricious  appetites,  who  tend  to 
eat  little  food  containing  anti-pellagric  substances,  and  persons,  who 
have  subsisted  on  diets  prescribed  by  physicians  for  certain  diseases,  diets 
which  fail  to  supply  adequate  amounts  of  the  pellagra-preventive  factor. 

5.  Persons  whose  requirements  for  the  anti-pellagric  substances  are 
increased.  Pregnancy,  lactation,  rapid  growth,  hyperthyroidism,  infec- 
tions and  increased  physical  exercise  are  all  factors  which  increase  the 
requirement. 

It  is  much  better  for  a  potential  pellagrin  to  eat  sufficient  amounts  of 
lean  meat,  eggs,  milk  and  vegetables  and  thus  prevent  the  disease  than 
it  is  for  him  to  have  to  be  treated  for  pellagra.  Satisfactory  diets,  taking 
into  consideration  the  daily  allowances  of  nutrients  recommended  by  the 
Council  on  Foods  and  Nutrition  of  the  National  Research  Council,  have 
been  planned  at  different  levels  of  cost  by  Carpenter  and  Stiebling'"^  and 
will  serve  as  an  excellent  guide  for  the  physician.  The  liberal  diet  plan 
which  they  suggest  provides  the  following  variety  in  the  course  of  the 
day  or  week: 
Milk: 

One  quart  daily  for  each  child  (to  drink  or  in  cooked  food) 
One  pint  daily  for  each  adult  (to  drink  or  in  cooked  food) 
Vol.  I.  948 


NICOTINIC  ACID  AAIIDE:  TREATAIENT  452(93) 

Vegetables  and  Fruits: 

Six  to  seven  servings  daily 

One  serving  daily  af  tomatoes  (^r  citrus  fruits 

Two  and  one-half  to  three  servings  daily  of  vegetables,  at  least 

half  of  which  are  leafy,  green  or  yellow  kinds 
Nine  to  ten  servings  a  week  of  fruit  (once  a  day,  sometimes 
twice) 
Eggs: 

Four  to  six  a  week;  also  some  in  cooking 
Meat,  fish  or  poultry: 

Once  a  day,  sometimes  twice 
Butter: 

At  every  meal 
Bread,  cereals,  and  desserts: 

As  needed  to  meet  calorie  requirements  or  as  desired  so  long 
as  they  do  not  displace  the  protective  foods 
.     In  areas,  in  which  pellagra  is  endemic,  the  authors  find  that  the  disease 
usually  occurs  in  persons  whose  diets  have  been  deficient  in  animal  pro- 
teins and  relatively  high  in  cereal  foods  and  fats. 

We  have  found  that  it  is  more  practical  to  add  to  the  existing  dietary 
daily  one-half  pound  ai  lean  meat,  two  eggs,  from  one  pint  to  one  quart 
of  milk  and  liberal  amounts  of  vegetables  than  it  is  to  try  to  change 
completely  long-established  dietary  habits.  AMien  such  additions  are  not 
available  or  practical,  we  have  found  that  daily  supplements  of  concen- 
trates such  as  dried  brewers'  yeast  or  liver  extract  are  excellent  preven- 
tive agents.  In  such  cases  we  recommend  two  ounces  of  dried  brewers' 
yeast  or  liver  extract.  Persons,  who  do  not  absorb  or  utilize  the  nutrients 
properly  or  whose  requirement  for  them  is  increased,  are  special  medical 
problems.  The  authors  have  found  that,  to  maintain  good  health  in  some 
cases,  it  is  sufficient  to  give  additional  amounts  of  the  foods  mentioned 
above.  In  others,  however,  the  administration  of  niacinamide  is  neces- 
sary. In  these  cases  we  usually  begin  with  an  oral  dose  of  from  20 
to  50  mgm.  daily.  In  those  rare  cases,  in  which  absorption  is  so  meager 
that  this  oral  dose  is  not  adequate,  20  mgm.  daily  is  given  by  intravenous 
injection.  In  administering  niacinamide  or  any  single  synthetic  sub- 
stance it  is  important  for  the  physician  always  to  keep  in  mind  that  the 
factors  which  predispose  to  or  precipitate  the  development  of  one  defi- 
ciency lead  to  the  development  of  others.  It  likewise  is  important  for  him 
to  realize  that  the  administration  of  niacinamide  alone  may  result  in  im- 
proved health,  but  it  will  not  restore  it  completely.  Thus,  for  every 
Vol.  I.  948 


452(94)  VITAMINS  AND  VITAMIN  DEFICIENCY 

pellagrin  or  every  potential  pellagrin  the  regular  consumption  of  a  liberal, 
well-balanced  diet  is  of  utmost  importance. 

The  dietary  treatment  of  patients  with  pellagra,  whether  they  are  in 
bed  at  home  or  in  the  hospital  or  whether  they  remain  ambulatory,  is 
based  on  the  principles  of  good  nutrition.  It  must  be  remembered,  how- 
ever, that  the  tissue  stores  of  niacinamide  as  well  as  of  the  other  essential 
nutrients  are  likely  to  be  severely  depleted.  Accordingly  the  diet  must 
supply  much  more  than  the  allowances  of  nutrients  recommended  for 
normal  persons.  We  recommend  that  the  diet  supply  from  3,000  to 
4,000  calories,  120  to  150  grams  of  protein  and  liberal  amounts  of  min- 
erals and  vitamins.  The  type  of  food  prescribed  and  the  form  in  which 
it  is  given  depend  entirely  upon  the  ability  of  the  patient  to  ingest  and 
retain  food.  Frequently  the  patient's  desire  for  food  is  absent,  and  he  has 
to  be  persuaded  to  eat.  In  the  severely  ill  patient,  the  mouth  and  tongue 
may  be  so  sensitive  that  only  soft  or  liquid  foods  can  be  tolerated,  and 
highly  seasoned  or  acid  foods  must  be  avoided.  In  some  instances  only 
a  small  amount  of  food  can  be  taken  at  one  time,  and  it  is  necessary  to 
give  small  feedings  at  frequent  intervals.  As  the  patient  improves,  semi- 
solid and  solid  foods  can  be  given.  In  all  cases  with  diarrhea  solid  foods 
should  be  added  as  soon  as  possible.  In  the  dietary  treatment  of  pellagra 
and  other  nutritional  deficiency  diseases,  we  have  found  the  following 
diets*  useful: 

4,000  Calorie  Liquid  Diet 

Suggested  Hourly  Feedings 

7  A.M.       Cereal  Gruel— i  serving  (see  recipe) 
Milk- 1  glass 

Eggnogg— I  glass  (see  recipe) 
Eggnogg— I  glass  (see  recipe) 
Ice  Cream 

Fruit  Juice  with  Egg  (see  recipe) 
Eggnogg— I  glass  (see  recipe) 
Cream  Soup— i  serving  (see  recipe) 
Milk— I  glass 
Eggnog— I  glass 
Ice  Cream— I  serving 
Eggnog— I  glass 

*  These  diets  were  planned  by  Miss  Jean  M.  Grant,  dietitian.  Nutrition  Clinic, 
Hillman  Hospital,  Birmingham,  Alabama. 

Vol.  I.  948 


8  AM. 

9  A.M. 

10  A.M. 

II  A.M. 

1 2  Noon 

I  P.M. 

2  P.M. 

3  P.M. 

NICOTINIC  ACID  AiVIlDE:    IREAIMENT  452(95) 

4  P.M.       Ice  Cream— I  serving 

5  P.M.       Cereal  Gruel— i  serving 

6  P.M.       Eggnog— I  glass 

7  P.M.       Cream  Soup— i  serving 
Ice  Cream— I  serving 

8  P.M.       Eggnog— I  glass 

9  P.M.       Eggnog— I  glass 
Note:  cup  =  standard  8  ounce  measuring  cup 

glass  =  8  ounce  water  glass 

Approximate  Food  Value  of  Diet 
Protein  145  gms. 

Total  Calories  4^134 

4,000  Calorie  Liquid  Diet 

Suggested  Feedings  Every  Two  Hours 

Fruit  Juice  with  egg— i  glass  (see  recipe) 
Cereal  Gruel— i  serving  (see  recipe) 
Eggnogg— I  glass  (see  recipe) 
Ice  Cream— I  serving 
Eggnogg— I  glass 
Milk— I  glass 

Cream  Soup— i  serving  (see  recipe) 
Eggnog— I  glass 
Ice  Cream— I  serving 
Eggnog— I  glass 
Milk— I  glass 
Eggnog— I  glass 
Ice  Cream— I  serving 
Cream  Soup— i  serving 
Ice  Cream— I  serving 
Eggnog— I  glass 
Cereal  Gruel— i  serving 
Eggnog— I  glass 
Eggnog— I  glass 
Note:   cup  =^  standard  8  ounce  measuring  cup 
glass  =  8  ounce  water  glass 

Approximate  Food  Value  of  Diet: 

Protein  145  gms. 

Total  Calories  4''34 

Vol.  I.  948 


7 

A.M. 

9 

A.M. 

[  I 

A.M. 

I 

P.M. 

3 

P.M. 

5 

P.M. 

7 

P.M. 

9 

P.M. 

1 1 

P.M. 

452(9^)) 


VITAMINS  AND  VITAMIN  DEFICIENCY 


Breakfast,  8  A.M. 


lo  A.M. 
Lunch,  12  Noon 


2  P.M. 
4  P.AI. 
Supper,  6  P.M. 


4,000  Calorie  "Soft-Solid"  Diet 

Suggested  Meals 

Fruit  Juice—  i  glass 
Cooked  Cereal— I  serving  (Yi  cup) 
Cream— 54  cup 
Sugar— 2  teaspoons 
Soft  Cooked  Eg^^s— 2 
Milk  Toast— Toast,   i  slice 

iMilk,  1/2  cup 

Butter,  I  square  (2  teaspoons) 
Milk— I  glass 
Coffee— if  desired 
Eggnogg— I  glass  (see  recipe) 
Ice  Cream  or  puddings—  i  serving 
Cream  Soup— i  serving  (see  recipe) 
Soft  Cooked  Eggs 
Milk  Toast— Bread,  i  slice 

Milk,  1/2  cup 

Butter,  2  teaspoons 
Mashed  Potato  or  Boiled  Rice  —  i  serving  (  Yi 

Butter—  I  pat  (2  teaspoons) 
Ice  Cream  or  Pudding  —  i  serving 
Milk  —  I  glass 
Eggnog  —  I  glass 
Eggnogg  —  I  s^lass 
Cream  Soup  —  i  serving 
Cooked  Cereal  —  Yz  cup 
Cream  —  Y4  cup 


cup) 


Sugar  —  2  teaspoons 
Soft  Cooked  Eggs  —  2 
Ice  Cream  or  Pudding  —  i  serving 
Milk  —  I  glass 
8  P.M.  Eggnog  —  I  glass 

Note:  cup  =  standard  8  ounce  measuring  cup 
Glass  =  8  ounce  water  glass 

Approximate  Food  Value  of  Diet: 
Proteins  147  gms. 

Total  Calories  4^i53 

Vol.  I.  948 


NICOTINIC  ACID  AMIDE:  TREATMENT  452(9?) 

4,000  Calorie  "Solid"  Diet 

Suggested  Me^Is  fn?d  Bet-coeeii  Meal  Feedings 

Breakfast  Fruit  Juice  -  i  glass 

Cereal  —  laro^e  servinir 
Eggs  —  2 

Bacon  or  Ham  -  if  desired 
Toast  —  2  slices 
Butter  —  2  pats 

Cream-  Vi  cup  (for  cereal  and  coffee) 
Milk  —  I  glass 
Coffee  —  if  desired 
10  A.M.  Eggnog-  I  glass  (see  recipe) 

Dinner  Lean  Meat,  Chicken  or  Fish  -  3  ounces 

Potato,  macaroni,  spaghetti,  noodles  or  dried  beans 

or  peas  ( i  serving) 
Vegetable  -  large  serving  (green  or  yellow  vege- 
table —  may   be   cooked   or  used   as   salad.    If 
cooked  add  i  square  of  butter;  if  used  as  salad, 
add  I  tablespoon  mayonnaise.) 
Bread  —  2  slices 
Butter  —  2  pats 
Dessert  —  i  serving 
Milk  —  I  glass 

2  P.M.  Eggnog  -  I  glass 

4  P.M.  Eggnog  -  I  glass 

Supper  Lean  Meat,  Chicken  or  Fish  -  3  ounces 

Potato,  macaroni,  spaghetti,  noodles  or  dried  beans 

or  peas  (i  serving) 
Vegetable  -  large  serving  (green  or  yellow  vege- 
table —  may   be   cooked   or   used   as   salad.     If 
cooked,  add  i  square  of  butter;  if  used  as  salad, 
add  I  tablespoon  mayonnaise.) 
Bread  —  2  slices 
Butter  —  2  pats 
Dessert  —  i  serving 
Milk  -  I  glass 
Vol..  1.  948 


452(98)  VITAMINS  AND  VITAMIN  DEFICIENCY 

I 

8  P.M.  Eggnog  —  I  glass 

Approximate  food  value  of  diet: 
Protein  148  Gm, 

Total  Calories  3,980 

Recipes 
Eggnog  6  eggs;  4  tablespoons  sugar;  6  cups  milk.  Beat  eggs. 

Add  sugar.   Add  milk.   Beat  mixture  well.   Choco- 
late syrup  or  vanilla  may  be  added,  if  desired.  Makes 
8  servings. 
Cereal  Gruel  V2  cup  of  any  kind  of  cooked  cereal  thinned  to  de- 

sired consistency  with  milk  and  served  with  V4  cup 
of  cream  and  with  sugar,  if  desired 
Cream  Soup  Y^   cup  strained  vegetable  or  canned  tomato,  pea, 

spinach  or  asparagus  soup.   Add  Yi  cup  cream. 
Fruit  Juice  Beat  i  egg  well.  Add  i  cup  fruit  juice.  Add  sugar 

with  Egg  as  desired. 

It  should  be  pointed  out,  however,  that  in  certain  diseases  such  as 
allergy,  diabetes  and  gastric  ulcer,  which  necessitate  restricting  the  kind 
or  amount  of  food,  these  diets  would  not  be  suitable.  Such  cases  require 
individual  diet  therapy,  a  detailed  discussion  of  which  is  beyond  the 
limits  of  this  chapter. 

Important  as  food  is  in  the  treatment  of  nutritive  failure,  therapy 
should  not  be  restricted  to  food  alone.  Deprivation  of  nutrients  usually 
has  existed  for  years,  and  the  average  patient  cannot  eat  enough  food  to 
supply  the  amount  of  these  nutrients  necessary  to  restore  his  health 
quickly.  Accordingly  supplements  of  the  nutrients,  in  which  the  diet  is 
deficient,  are  given.  Until  synthetic  vitamins  became  available,  dried 
brewers'  yeast  powder,  wheat  germ,  liver  concentrates  and  citrus  fruit 
were  given  in  treating  deficiencies  of  the  water-soluble  vitamins.  As 
valuable  as  these  substances  were,  and  still  are,  there  are  times  when 
niacinamide  is  life-saving. 

The  amount  of  niacinamide  or  similar  compounds  necessary  for  a 
therapeutic  response  in  pellagra  varies  tremendously  from  patient  to 
patient  so  that  no  arbitrary  dosage  can  be  set.  In  the  average  case  we 
have  found  that  50  mgm.  administered  orally  10  times  a  day  is  effective. 
Oral  administration  of  niacinamide  is  preferable  to  other  methods,  be- 
cause by  this  route  it  is  absorbed  more  slowly,  and  an  elevated  blood 
concentration  is  maintained  over  a  longer  period  of  time  than  it  is  when 

Vol.  I.  948 


NICOTINIC  ACID  AMIDE:  TOXICITY  452(99) 

it  is  administered  bv  any  other  route.  We  have  observed  one  patient  with 
long-standing  pellagra,  however,  who  failed  to  respond  to  oral  doses  of 
niacinamide  as  high  as  1,500  mgm.  daily,  but  who  improved  rapidly  fol- 
lowing the  intravenous  administration  of  50  mgm.  6  times  a  day. 

Parenteral  therapy  is  indicated,  when  a  high  blood  concentration  is 
desired  within  a  short  period  of  time,  when  gastrointestinal  absorption 
is  inadequate,  or  when  the  patient  is  in  stupor  or  coma.  In  such  cases 
50  to  100  mgm.  doses  are  sufficient.  In  order  to  keep  the  blood  concen- 
tration at  a  high  level,  it  should  be  administered  in  small  doses  at  frequent 
intervals.  The  authors  give  50  mgm.  doses  4  times  daily  and  inject  it 
slowly.  When  parenteral  administration  of  saline  or  glucose  is  indicated 
in  the  acutely  ill  patient,  the  vitamin  can  be  dissoh'ed  in  a  physiological 
solution  of  saline  or  5  per  cent,  glucose  and  administered  by  slow  drip. 
Niacinamide  can  be  given  intramuscularly  in  the  same  dosage  as  that 
suggested  for  intravenous  injection.  Intramuscular  therapy  is  not  recom- 
mended for  persons  with  deficiency  disease,  however,  because  it  is 
attended  by  some  risk  of  abscess  formation  in  devitalized  tissues. 

A  satisfactory  daily  dose  for  infants  is  from  50  to  100  mgm.  dissolved 
in  the  infant's  total  milk  supply  for  the  day.  For  parenteral  administra- 
tion we  suggest  15  mgm.  3  times  a  day.  If  the  infant  is  breast  fed,  the 
niacinamide  can  be  given  to  the  nursing  mother".  This  increases  the 
niacinamide  content  of  the  mother's  milk  sufficiently  to  relieve  the 
infant's  deficiency.  For  children  two  or  three  times  the  dose  recom- 
mended for  infants  is  suggested  and  should  depend  upon  the  size  of  the 
child. 

Adequate  doses  of  niacinamide  or  similar  substances  administered  to 
a  pellagrin  will  (a)  cause  fading  of  the  fiery  redness  of  the  mucous 
membrane  lesions  and  disappearance  of  the  associated  Vincent's  or- 
ganisms, (b)  cause  disappearance  of  the  acute  mental  symptoms  of 
pellagra  such  as  delirium,  hallucinations  and  mental  confusion,  (c)  re- 
lieve diarrhea,  vomiting  and  cramping,  w^hich  arise  from  alterations  in 
alimentary  function,  (d)  cause  fading  of  the  dermal  erythema,  (e) 
increase  the  feeling  of  strength  and  well-being,  (f )  result  in  disappear- 
ance of  certain  ether-soluble  red  pigments  from  the  urine,  (g)  increase 
the  concentration  of  co-enzymes  I  and  II  in  whole  blood  and  urine  and, 
when  therapy  is  prolonged,  increase  the  co-enzyme  content  of  the 
muscle.  We  wish  to  stress,  however,  that  in  treating  pellagra  or  any 
other  nutritional  deficiency  disease,  the  patient  as  well  as  his  disease  must 
be  treated. 
Vol.  I.  948 


452 (loo)         VITAMINS  AND  VITAMIN  DEFICIENCY 

Toxicity 

Nicotinic  acid,  in  the  amounts  recommended  for  therapy,  is  not  toxic 
althoiiorh  it  and  all  related  compounds  containing  the  free  radical  produce 
vasodilation  in  the  skin  and  an  increase  in  skin  temperature  as  already 
illustrated  by  Figure  36. 


Vol.  I.  948 


RIBOFLAVIN:  HISTORY  452(101) 

RIBOFLAVIN 

I  lis  PdRY 

The  scientific  world  p;iid  scant  attention  when  Blythc"",  the  LngUsh 
chemist,  reported  the  presence  of  a  fluorescent,  yellow-green  substance 
in  milk  in  1867.  Blythe  himself  was  interested  primarily  in  learning- 
something  about  the  composition  of  milk,  and  little  did  he  realize  that 
the  pigment,  which  he  described,  would  later  play  a  role  in  the  science 
of  nutrition.  Although  chemists"'^"  again  studied  this  yellow  material  in 
1925  and  described  some  of  its  properties,  its  biochemical  nature  re- 


/  L   „         ■ 

Fig.  38.     Crystalline  riboflavin  (courtesy  of  Merck  and  Co.). 

mained  to  be  disclosed  through  a  different  source.  In  1932  \\  arburg  and 
Christian'^^  described  a  new  "yellow  enzyme"  which  they  obtained  from 
the  aqueous  extract  of  bottom  yeasts.  It  proved  to  be  one  of  the  most 
ubiquitous  of  the  enzymes  concerned  in  cellular  respiration,  and  these 
investigators  later  separated  this  yellow  enzyme  into  a  protein  compo- 
nent and  a  pigmented  portion  and  noted  that  neither  alone  was  active. 
In  1933  Kuhn  and  his  co-workers  isolated  the  pigment  from  natural 
sources'^",  and  in  1935  Karrer  and  his  collaborators-'*"'  and  Kuhn  and  his 
associates"^*  independently  synthesized  riboflavin. 

Chemistry  and  Physiology 

Riboflavin  crystallizes  in  fine  yellow  needles  which  melt  at  282°  C. 
(Fig.  38).  The  structural  formula  of  riboflavin  is  sho\Mi  in  Figure  39. 
The  pure  compound  is  only  slightly  soluble  in  water  and  ethyl  alco- 
hol and  is  very  soluble  in  alkali  solutions.  It  is  insoluble  in  acetone,  ether. 

Vol.  I.  948 


452(102)         VITAMINS  AND  VITAMIN  DEFICIENCY 

benzene  and  chorofomi.  The  water  solution  is  of  greenish-yellow  color 
and  has  an  intense  yellow-green  fluorescence  which  disappears  with  the 
addition  of  either  acids  or  alkalis.  Light  slowly  destroys  the  vitamin 
activity.  The  decomposition  is  influenced  also  by  temperature  and  by 
the  hydrogen  ion  concentration.  It  has  a  relatively  high  thermostability. 
Under  ultra-violet  light  riboflavin  emits  a  blue-green  fluorescence. 
It  is  on  this  property  that  the  fluorometric  quantitative  determination  of 
the  substance  depends.  A  second  accurate  method  of  quantitation  is 
based  upon  the  conversion  of  riboflavin  to  lumiflavin  by  exposure  to 
light  in  alkaline  solution.   The  amount  of  lumiflavin  then  can  be  deter- 


H      M     M     M      M 
HC-C-C-C-COH 
0     0     0     H 
H      M      H 

H 

,0                  N                 iN 

/   \/    \/   \ 
HsC— c         c         c         c  =  o 

1         II         1         > 

1           II 
HjC— C           C 
\    /\ 

c         ^ 

H 

1        1 

C           N  — H 
/\   / 

J        c  =  o 

Fig.  39.     Structural  formula  of  d-riboflavin   (6,7-dimethvl-9    (I'-d-ribityD-isoalloxa- 
zine). 

mined  colorimetrically.  A  microbiological  assay  measures  the  acid  pro- 
duction by  Lactobacillus  casei;  this  is  proportional  to  the  amount  of 
riboflavin  present  in  the  system. 

Riboflavin  takes  part  in  many  different  enzyme  systems  in  the  tissues. 
Each  system  consists  of  an  apoenzyme  and  a  coenzyme.  The  apoenzyme 
is  a  specific  protein  or  the  "Zwischenferment".  The  coenzyme  consti- 
tutes the  prosthetic  group  of  the  enzyme  system,  and  riboflavin  is  an 
integral  part  of  its  constitution.  The  same  coenzyme  can  serve  as  the 
prosthetic  group  of  a  number  of  different  apoenzymes. 
The  two  coenzymes  containing  riboflavin  are  (i)  riboflavin-5'- 
phosphoric  acid  (riboflavin-mononucleotide)  and  (2)  riboflavin-ade- 
nine-dinucleotide.  Riboflavin  acts  on  the  various  enzyme  systems  by 
reversibly  accepting  and  donating  two  atoms  of  hydrogen.  This  is 
accomplished  by  the  addition  of  the  hydrogen  to  the  one  and  ten  posi- 
tions of  riboflavin.  Riboflavin  is  the  only  naturally-occurring  flavin  with 
vitamin  B2  activity.  A4any  flavin  compounds  have  been  prepared  syn- 
thetically and  shown  to  have  vitamin  activity.  Generally  speaking  sub- 
stitution in  the  six  or  seven  position  is  necessary  for  vitamin  activity,  and 

Vol.  I.  948 


RIBOFLAVIN:  CHEMISTRY  AND  PHYSIOLOGY    45^(103) 

the  absence  of  substituents  in  both  positions  is  accompanied  by  toxicity. 
An  LinsLibstituted  group  in  the  three  position  also  is  necessary  for  activity. 
Riboflavin  is  a  combination  of  d-ribose  and  isoalloxazine.  The  phos- 
phoric acid  ester  of  riboflavin  unites  a  specific,  nonactivc,  bearer  protein 
to  form  the  "yellow  enzyme".  In  the  presence  of  an  "activating  enzyme" 
from  yeast  (Zwischenfemient)  and  a  thermostable  coenzyme  (now 
identified  as  coenzyme  II,  triphosphorpyridine  nucleotide)  the  yellow 
enzyme  is  capable  of  oxidizing  Robinson's  hexose  monophosphoric  ester. 
The  following  scheme  has  been  postulated  for  the  action  of  this  system: 

Zwischcnfermcnt 

( 1 )  coenzyme  +  hexose  monophosphoric  acid >-  reduced 

coenzyme-phosphohexonic  acid 

(2)  reduced  coenzyme  +  yellow  enzyme >- coenzyme + 

reduced  yellow  enzyme 

(3)  reduced  yellow  enzyme  +  molecular  oxygen >- H2O2  + 

yellow  enzyme 
This  system,  in  contrast  to  other  well-known  oxidation-reduction  sys- 
tems, is  not  poisoned  by  hydr/jcyanic  acid  or  carbon  monoxide.  Since 
the  coenzyme  is  alternately  reduced  and  oxidized  by  the  yellow  enzyme, 
and  the  yellow  enzyme  itself  is  reversibly  oxidized  and  reduced,  only  a 
very  small  amount  of  both  of  these  substances  is  required  for  the  reaction. 

In  similar  enzyme  systems  the  flavoprotein  is  concerned  with  oxida- 
tion of  amino  acids.  It  combines  with  phosphoric  acid,  ribose  and 
adenine  to  form  a  d-amino  oxidase.  A  similar  dinucleotide  has  been 
described,  which  catalyzes  the  oxidation  of  aldehydes  and  lactic  acid. 
Another  flavoprotein  enters  the  metabolism  of  xanthines  as 'an  oxidase. 
A  number  of  flavoproteins  have  been  described  chemically;  some  are 
inactive,  and  the  biological  importance  of  others  has  not  been  established. 

Riboflavin  occurs  naturally  in  three  forms;  as  riboflavin  per  se,  as 
riboflavin-5 '-phosphoric  acid  and  as  riboflavin-adenine-dinucleotide.  It 
may  be  absorbed  easily  by  the  intestine  in  any  of  these  fomis.  The 
transformation  of  riboflavin  to  its  phosphoric  acid  ester  and  the  dinu? 
cleotide  is  a  general  cellular  reaction.  Human  blood  cells,  for  example, 
can  make  the  synthesis  in  vivo  or  in  vitro,  but  the  plasma  cannot.  This 
means  that  riboflavin  can  be  administered  parenterally,  and  we  often  do 
this. 

It  would  seem  that  the  liver  and  kidney  are  the  organs  most  con- 
cerned with  the  use  of  riboflavin  and  other  substances  to  form  specific 
enzyme  systems.  Riboflavin  is  excreted  chiefly  in  the  feces.  A\'hen  the 
diet  is  low  in  riboflavin,  practically  no  riboflavin  is  excreted  in  the  urine, 

Vol.  I.  948 


452(104)         VITAMINS  AND  VITAMIN  DEFICIENCY 

although  it  is  still  found  in  the  feces.  An  increase  in  the  riboflavin  intake 
of  human  beings  is  followed  rapidly  by  an  increase  in  the  urinary  output. 
The  animal  organism  apparently  has  no  special  storage  organ  for  ribo- 
flavin, although  the  blood  level  is  maintained  in  spite  of  lesions  in  man. 
Larger  concentrations  are  found  in  the  liver  and  in  the  kidney,  although 
a  large  intake  of  riboflavin  does  not  increase  its  content  to  any  great 
extent.  Even  when  animals  die  from  lack  of  this  vitamin,  their  tissues 
still  contain  considerable  amounts,  often  as  much  as  one-third  of  the 
normal  level.  No  substantial  decrease  of  the  riboflavin  content  of  the 
blood  and  muscles  could  be  observed  in  man  even  though  they  had 
clinical  lesions"'^ 

If  the  intake  from  the  gastrointestinal  tract  is  increased  greatly,  there 
is  only  a  slight  increase  in  the  amount  stored.  As  long  as  the  diet  is 
adequate,  riboflavin  is  excreted  in  the  urine.  On  a  low  dietary  intake  the 
excretion  exceeds  the  intake  but  gradually  decreases.  The  body  clings 
tenaciously  to  its  stores  of  riboflavin.  Axelrod,  Spies  and  Elvehjeni"^^ 
could  not  detect  a  correlation  between  the  amount  of  a  test  dose  of 
riboflavin  retained  and  the  daily  urinary  riboflavin  excreted  in  human 
beings.  They  did  produce  uncomplicated  riboflavin  deficiency  in  the 
dog,  however,  in  which  the  degree  of  retention  of  a  test  dose  of  ribo- 
flavin was  found  to  be  a  measure  of  the  riboflavin  deficiency. 

Riboflavin  is  distributed  so  widely  that  it  seems  that  each  animal  and 
plant  cell  contains  small  amounts.  The  amount  in  the  seeds  of  plants  is 
small  but  increases  rapidly  during  germination.  The  richest  source  of 
riboflavin  is  certain  fermentation  bacteria.  Yeast  contains  considerable 
amounts.  .The  liver,  kidney  and  heart  contain  about  ten  to  thirty  times 
the  amount  found  in  muscles.  The  retina  of  the  eyes  of  many  species  of 
animal  contains  large  quantities  of  riboflavin.  Riboflavin  tends  to  be 
found  in  the  free  form  in  human  milk,  in  the  urine  and  in  the  retina. 

Canning  processes  cause  the  loss  of  from  22  to  67  per  cent,  of  the 
riboflavin  in  foods.  Ordinary  cooking,  ho\\'ever,  destroys  but  little,  and 
the  only  loss  of  magnitude  occurs  in  the  event  that  water,  in  which  food 
has  been  boiled,  is  discarded.  Freezing  of  foods  for  storage  does  not  alter 
appreciably  their  riboflavin  content. 

Pathological  Physiology 

There  has  been  so  little  investigation  of  the  histological  changes  in 
human  tissues  in  riboflavin  deficiency  that  a  pathological  description  is 
not  available.   Studies  of  gross  living  material,  particularly  the  eye  and 

Vol.  I.  948 


RIBOFLAVIN:  PATHOLOGICAL  PHYSIOLOGY    452(105) 

tongue,  have  been  made  using  tlie  slit-l;inip  biomicroscope.  These  reveal 
the  nonspecific  changes  so  often  acconipanying  inflanmuuion  and  atro- 
phy. Although  our  kno\^ledge  of  the  pathological  ph\  siologv  is  fai 
from  complete,  it  is  believed  that  the  cornea  and  other  relativciv  avascu 
lar  tissues  are  dependent  to  a  great  extent  on  the  Havoprotein  for  normal 
respiration.  This  may  explain  the  vascularization  around  the  cornea  in 
individuals  which  is  relieved  by  riboflavin. 

Until  recently  little  precise  scientific  knowledge  has  existed  in  regard 
to  the  assumption  that  congenital  anonralies  may  occur  as  a  result  of  a 
deficiency  of  riboflavin  in  the  maternal  diet.  W'arkany  and  associates"'*^'^' 
have  shown  that  female  rats  on  restricted  diets  gave  birth  to  \()ung  with 
skeletal  defects.  Malformations  occurred  in  the  extremities,  the  jaw  and 
the  ribs,  and  there  was  a  constant  type  of  cleft  palate.  These  authors 
have  shown  that  the  malformations  could  be  prevented  completely  by 
giving  riboflavin.  One  of  the  most  interesting  aspects  of  these  studies 
has  been  the  determination  of  the  actual  period  of  embryonic  develop- 
ment in  which  the  deficiency  of  riboflavin  results  in  abnormal  tissue 
differentiation.  They  found  that  the  mother  rat  still  could  produce  nor- 
mal young,  if  the  deficient  diet  was  corrected  on  the  twelfth  day  of 
gestation.  The  thirteenth  day  was  the  critical  day;  adding  the  supple- 
ment on  the  fourteenth  day  or  any  day  thereafter  failed  to  protect  the 
young.  The  implications  of  these  dramatic  experiments  with  respect  to 
maternal  human  nutrition  are  tremendous.  It  would  seem  that  it  is  not 
enough  that  the  mother  be  able  to  conceive;  she  must  have  adequate 
nutrients  for  normal  difl^erentiation  and  for  nomial  reproduction. 

It  is  highly  probable  that  riboflavin  may  constitute  a  part  of  many 
enzymes  other  than  Warburg's  yellow  enzyme,  xanthine  oxidase  and 
d-aminoacid  oxidase.  This  postulate  might  explain  the  all  too  frequent 
cheilosis  which  is  not  healed  by  riboflavin.  Under  such  circumstances  it 
may  be  that  the  system  of  hydrogen  carriers  and  acceptors  is  disrupted 
at  a  point  close  to  the  active  position  of  riboflavin  and  that  similar  patho- 
logical lesions  are  produced  even  when  the  supply  of  riboflavin  is  ade- 
quate or  excessive.  There  is  some  suggestion  that  pyridoxine  (vitamin 
Be)"^^  or  iron  may  fit  into  such  auxiliary  systems. 

The  theory  that  the  ocular  lesions  of  riboflavin  deficiency  result  from 
anoxia  has  been  advanced'"^;  the  engorgement  of  the  conjunctivae  and 
limbal  vessels  may  be  considered  an  inadequate  attempt  to  supply  the 
tissues  in  this  area  with  adequate  oxygen.  Thus,  one  might  expect  a 
deficiency  of  almost  any  enzyme  to  produce  similar  ocular  si«;-ns.  It  is 
equally  possible,  however,  that  riboflavin  may  aid  in  the  formation  of 

Vol.  I.  948 


452 (io6)         VITAA/IINS  AND  VITAMIN  DEFICIENCY 

choline  esterase  and  through  its  action  on  acetylchoHne  and  the  auto- 
nomic nervous  system  effect  conjunctival  vasodilitation. 

Since  it  was  demonstrated  that  riboflavin  is  synthesized  by  bacteria 
in  the  rumens  of  animals,  it  has  been  suspected  that  this  might  occur  in 
the  intestinal  tract  of  man.  There  has  been  some  indirect  evidence  to 
substantiate  this  hypothesis'^*".  The  authors  have  been  unable  to  deter- 
mine the  amount  of  riboflavin  produced  by  intestinal  bacterial  synthesis. 
The  type  of  bacterial  flora  and  the  quality  of  the  diet  are  important,  but 
it  has  not  been  determined  whether  or  not  the  body  can  utilize  the  ribo- 
flavin present  in  viable  bacteria. 


Symptomatology 

Perhaps  the  most  characteristic  clinical  sign  in  riboflavin  deficiency 
is  an  angular  stomatitis  which  is  called  cheilosis-".  The  earliest  change 
is  a  paleness  of  the  lips,  particularly  at  the  angles  but  not  the  moist  area 
of  the  buccal  mucosa.  The  pallor  usually  continues  for  days  and  is  fol- 
lowed by  maceration  and  piling  up  of  whitish  tissue  on  a  pink  back- 
ground. Superficial  fissures  may  invade  the  site  of  the  natural  wrinkles 
at  the  corners  of  the  mouth.  The  macerated  lesions  subsequently  become 
dry,  and  a  yellowish  crust,  which  forms  at  the  angles,  can  be  removed 
without  causing  bleeding.  As  the  disease  progresses,  the  fissures  in  the 
corners  of  the  mouth  tend  to  become  deeper  and  extend  to  the  cheek. 
They  may  extend  within  the  mouth  so  that  the  constantly  irritated  angles 
become  raw,  bleeding  areas  with  crusts  or  scabs.  Such  lesions  are  some- 
times very  painful  in  the  acute  stage.  Frequent  recurrences  may  result 
in  the  formation  of  a  cicatrix,  giving  the  affected  area  an  atrophic  appear- 
ance. Cheilosis  usually  occurs  at  both  angles  of  the  mouth,  but  some- 
times only  one  angle  is  involved  (See  Fig.  40).  Furthermore,  there  may 
be  a  difference  in  severity  of  the  lesions  at  the  two  angles  of  the  mouth, 
and  in  occasional  cases  the  lesion  at  one  angle  progresses  while  the  other 
regresses.  Another  alteration  occurs,  usually  in  the  inner  surface  of  the 
lower  lip;  apparently  with  the  shedding  of  superficial  epithelium  the 
mucous  border  becomes  a  brilliant  red.  On  close  examination  one  finds 
this  to  be  caused  by  increased  visibility  of  a  myriad  of  minute  dilated 
vessels.  This  rarely  is  associated  with  burning  of  the  lips  and  tongue. 
The  lesions  of  the  lips  and  the  angles  of  the  moutli  often  heal  sponta- 
neously in  the  winter  and  summer  and  break  down  in  the  spring  and 
fall,  and  persons,  whose  lips  have  undergone  these  changes  repeatedly. 

Vol.  I.  948 


Fig.  40.     Cheilosis  from  riboflavin  deticiency, 


RIBOFLAVIN  SYMPTOMATOLOGY  45.2  (>  07) 

show  scarring  in  the  angles  of  the  mouth  and  mottling  of  the  vermihon 
border  of  the  hps. 

Such  pathological  changes  at  the  angles  of  the  mouth  have  been  called 
"perleche,"  which  means  "to  lick  intensively".  Epidemics  of  perleche 
have  been  described,  particularly  in  children's  institutions.  In  one  such 
epidemic  Finnerud"^'  called  attention  to  a  seborrhoeic  dermatitis-like 
eruption  of  the  face  in  18  of  100  children  with  perleche.  In  1944  he 
reviewed  the  etiology  of  perleche  and  emphasized  its  polyetiological 
nature-^^  Such  lesions  of  the  angles  of  the  mouth,  which  heal  with  ribo- 
flavin, also  yield  smears  and  cultures  positive  for  yeast,  fungi  and  bac- 
terial organisms  such  as  staphylococci,  streptococci  and  Vincent's  or- 
ganisms. 

Cheilosis  of  a  mechanical  etiology  must  be  differentiated  from  that 
caused  by  riboflavin  deficiency.  This  type  has  been  studied  by  Ellenberg 
and  Pollack^**  and  by  Mann  and  Spies-*^  and  it  has  been  related  directly 
to  a  decrease  in  the  vertical  dimension  of  the  face  in  many  instances  due 
to  ill-fitting  dentures,  only  one  denture  or  none  at  all.  Thus,  consump- 
tion of  an  adequate  amount  of  a  varied  diet  often  was  impossible.  When 
these  patients  were  given  riboflavin,  there  was  an  amelioration  of  the 
cheilosis,  but  the  lesions  did  not  disappear.  W'ith  sagging  of  the  facial 
muscles  and  the  resultant  fissures  at  the  angles  of  the  mouth  saliva  readily 
leaks  into  the  intertriginous  areas,  and  maceration  and  infection  result. 
It  is  necessary  to  restore  adequate  dental  function  and  a  normal  contour 
of  the  face  in  order  to  facilitate  the  healing  of  the  lesions  in  these  persons. 
It  is  only  under  such  circumstances  that  they  can  ingest  the  foods  neces- 
sary to  maintain  optimal  nutrition. 

Often  the  prominence  of  the  papillae  is  reduced,  and  the  tongue  has 
a  smooth  appearance.  It  may  be  purplish  red  or  magenta  in  color.  Irreg- 
ular patches  of  erythema  may  be  present,  but  they  are  not  as  fiery  red  as 
they  are  in  nicotinic  acid  amide  deficiency.  Frequently  the  glossitis  of 
pellagra  obscures  that  of  riboflavin  deficiency,  and  it  is  not  until  the 
pellagrous  erythema  has  blanched  following  the  administration  of  nico- 
tinic acid  that  the  underlying  purplish  color,  characteristic  of  riboflavin 
deficiency,  can  be  seen.  Clinical  trial,  first  with  nicotinic  acid  and  then 
with  riboflavin,  often  is  necessary  in  order  to  distinguish  the  glossitis  of 
pellagra  from  the  glossitis  of  riboflavin  deficiency. 

The  first  statement  in  regard  to  certain  eye  symptoms  arising  in  per- 
sons with  riboflavin  deficiency  is  that  of  Spies,  Bean  and  Ashe  in  1939"^*. 
They  described  a  series  of  symptoms  which  disappeared  within  forty- 
eight  hours  after  a  single  injection  of  riboflavin  and  returned  within  ten 
Vol.  I.  948 


452 (loS)         VITAMINS  AND  VITAMIN  DEFICIENCY 

to  twenty  days,  if  the  deficient  diet  was  continued.  The  syndrome  was 
greatly  ampHfied  by  Spies,  Vilter  and  Ashe'"  the  same  year.  They  called 
attention  to  ocular  manifestations  of  riboflavin  deficiency  in  human 
beiniTs.  These  manifestations  included  bulbar  conjunctivitis,  dilatation  of 
the  conjunctival  vessels,  burning  of  the  eyes,  lacrimation,  failing  vision 
and  extreme  photophobia.  All  the  patients  studied  were  known  to  have 
been  on  a  riboflavin-deficient  diet,  and  their  symptoms  disappeared  fol- 
lowing riboflavin  therapy.  Soon  many  investigators  reported  studies  on 
riboflavin  deficiency,  and  the  next  year  Kruse,  Sydenstriker,  Sebrell  and 
Cleckley-*^  reported  on  nine  patients  and  stated  that  the  principal  mani- 
festation was  keratitis.  Later  that  year  these  investigators  reported  that 
by  means  of  the  slit  lamp  they  had  found  vascularization  of  the  cornea. 
They  stressed  particularly  the  superficial  vascularization  of  the  cornea 
and  the  finding  of  interstitial  keratitis.  Unfortunately  these  investigators 
apparently  did  not  examine  the  corneas  of  a  large  number  of  patients, 
for  today  there  is  much  controversy  on  the  subject  and  a  wide  divergence 
of  opinion.  Many  ophthalmologists  have  refused  to  accept  the  specificity 
of  these  ocular  lesions. 

A  study  of  500  patients  with  the  ocular  manifestations  of  riboflavin 
deficiency  by  Spies,  Perry,  Cogswell  and  Frommeyer'^'^  shows  that  these 
lesions  frequently  occurred  in  the  absence  of  cheilosis  or  vice  versa.  The 
visual  symptoms  in  practically  all  the  patients  were  heralded  by  a  feeling 
of  dryness  of  the  eyes  which  was  followed  by  burning  and  itching  and 
sometimes,  by  photophobia  and  lacrimation.  In  some  cases  conjunctivitis 
was  the  sole  manifestation  and  was  shown  by  increased  visibility  of  the 
vessels  of  both  the  bulbar  and  palpebral  conjunctivae,  apparently  due  to 
congestion  and  dilatation.  Small  vessels  were  observed  to  encroach  on 
the  cornea  at  the  scleral-corneal  junction.  Interstitial  keratitis  was  ob- 
served in  60  per  cent,  of  the  patients  and  corneal  ulceration  in  at  least  one 
eye  in  53  per  cent.  In  all  cases  an  effort  was  made  to  eliminate  other 
etiological  disorders  such  as  vernal  conjunctivitis,  foreign  bodies  in  the 
cornea,  xerophthalmia  and  such  diseases  of  the  uveal  tract  as  iritis  due  to 
syphilis,  tuberculosis  and  rheumatic  fever. 

Within  forty-eight  hours  after  beginning  therapy  there  was  some 
subjective  improvement  in  all  the  patients.  Improvement  was  volun- 
teered in  80  per  cent,  of  the  cases.  Within  this  period  a  diminution  in 
the  calibre  of  the  dilated  vessels  in  the  eyes  and  a  striking  decrease  in  the 
photophobia  and  corneal  ulcerations  were  observed.  Accompanying^  this 
improvement  was  a  decrease  of  hemolytic  staphylococci,  streptococci 
and  xerosis  bacilli  in  the  exudate  from  the  eyes.  Relief  of  pain  occurred 

Vol.  I.  948 


RIBOFLAVIN:  DIAGNOSIS  452(109) 

and  vision  improved.  Although  84  per  cent,  of  the  patients  subsequently 
had  recurrences,  this  is  attributed  to  cessation  of  therapy  and  a  return 
to  the  previous  diet  which  was  inadequate  in  riboflavin. 

It  must  be  emphasized  that  the  differentiation  of  these  superficial 
lesions  of  the  eye  from  other  types  of  conjunctivitis  and  keratitis  is  both 
difficult  and  uncertain.  It  seems  that  many  other  varieties  of  conjunc- 
tivitis also  may  be  benefited  by  the  parenteral  administration  of  riboflavin 
which  suggests  that  this  vitamin  may  play  a  routine  part  in  such  inflam- 
mations. 

Diagnosis 

In  making  a  diagnosis  the  physician  should  keep  in  mind  that  ribo- 
flavin deficiency  may  occur  in  either  sex,  at  any  age  and  in  any  race,  that 
it  usually  occurs  following  subsistence  for  months  or  years  on  a  diet 
deficient  in  riboflavin,  and  that  it  is  especially  common  anions^  those 
whose  diets  are  inadequate.  It  may  occur,  however,  as  a  result  of  a 
metabolic  complication  of  some  other  disease  state,  and  in  such  cases  it 
is  referred  to  as  secondary  riboflavin  deficiency.  The  physiological  pos- 
sibilities for  the  induction  of  a  secondary  deficiency  may  be  listed  briefly 
as  follows;  (a)  decreased  intake,  (b)  decreased  absorption,  (c)  increased 
excretion,  (d)  increased  requirement,  (e)  decreased  utilization,  (f)  in- 
creased destruction. 

In  a  report  describing  observations  on  500  selected  cases  of  riboflavin 
deficiency  Spies,  Perry,  Cogswell  and  Frommever*^  found  that  the 
dietaries  of  these  patients  supplied  only  one-third  of  the  allowance  of 
riboflavin  recommended  by  the  Food  and  Nutrition  Board  of  the  Na- 
tional Research  Council  (see  Fig^.  41). 

What  should  constitute  the  exact  criteria  for  the  diagnosis  of  human 
riboflavin  deficiency  is  almost  impossible  to  estimate  from  the  various 
reports.   SebrelF'"  has  summarized  his  concept  as  follows: 

"(i)  Ocular  lesions,  consisting  usually  of  a  vascularizing  keratitis 
with  photophobia,  dimness  of  vision,  severe  injection  of  the  vessels  of 
the  fornix  and  sclera,  burning  of  the  eyes,  lacrimation,  and  in  severe 
cases,  opacities  of  the  cornea;  (2)  oral  lesions,  consisting  usually  of 
linear  fissures  in  the  angles  of  the  mouth,  a  reddened,  shiny,  denuded 
appearance  of  the  lower  lip,  and  a  flattening  of  the  papillae  of  the 
tongue,  which  becomes  magenta  red  in  color;  (3)  dermal  lesions, 
consisting  usually  of  seborrheic  accumulations  in  the  folds  of  the  skin, 
especially  in  the  nasolabial  folds,  around  the  eyelids,  on  the  ears,  and 
Vol.  I.  948 


452 (no)         VITAMINS  AND  VITAMIN  DEFICIENCY 


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and  Nutrition  Board,  National  Research  Council. 


Food 


Vol.  I.  948 


RIBOFLAVIN:  PREVENTION  AND  TREATMENT  452  ( 1 1 1 ) 

in  some  cases  comedones  and  a  sharkskin-appearing  lesion  on  the  nose 
and  over  the  malar  eminences.    In  some  cases  the  seborrheic  dermal 
lesions  may  be  extensive  and  may  involve  other  regions  of  the  body." 
In  the  absence  of  characteristic  lesions  the  recognition  of  riboflavin 
deficiency  is  difficult.  An  appraisal  of  the  dietary  of  the  patient  is  help- 
ful but  not  an  infallible  guide.   The  scars  of  old  cheilosis  should  arouse 
suspicion.    In  the  prodromal  period  prior  to  the  appearance  of  typical 
lesions  most  of  the  subjective  symptoms  result  from  depletion  of  niacin- 
amide and  thiamine  stores.    Neither  at  this  period  nor  later,  when  the 
lesions  are  advanced,  is  there  a  consistently  accurate  laboratory  test  to 
determine  the  adequacy  or  inadequacy  of  the  stores  of  riboflavin. 

A  tentative  diagnosis  is  warranted  in  the  presence  of  cheilosis  with 
angular  stomatitis,  engorgement  of  pericorneal  vessels  and  concommitant 
subjective  symptoms  of  photophobia,  burning  and  dimness  of  vision. 
Riboflavin  deficiency  should  be  suspected  in  the  person,  who  presents 
a  magenta  tongue  or  the  greasy,  scaly  dermatitis  in  characteristic  areas 
about  the  face  and  the  "sharkskin"  appearance  of  skin  over  the  nose  and 
malar  prominence.  In  examining  the  tongue,  however,  it  should  be  kept 
in  mind  that  forceful  protrusion  results  in  compression  of  the  ranular 
veins  and  in  congestion  and  cyanosis.  Therefore,  the  magenta  hue  should 
be  observed  in  the  tongue  at  rest  within  the  mouth. 

The  therapeutic  test  substantiates  the  diagnosis.  Healing  of  the  angles 
of  the  mouth  and  the  tongue  usually  is  initiated  after  from  three  to  six 
days  of  specific  therapy.  Subjective  improvement  in  the  ocular  lesions 
usually  is  noticeable  in  24  hours,  if  large  doses  are  given,  although  objec- 
tively there  may  be  little  change  for  from  two  days  to  a  week.  Complete 
healing  of  the  eye  and  skin  lesions  extends  over  a  period  of  several  weeks, 
and  the  conjunctivitis  is  prone  to  relapse  m  hen  treatment  is  discontinued. 


Prevention  and  Treataient 

Riboflavin  deficiency  can  be  prevented  either  by  the  use  of  synthetic 
riboflavin  or  by  the  consumption  of  foods  rich  in  riboflavin.  The  prac- 
ticing physician  is  urged  to  read  the  sections  on  vitamin  Bi  and  nicotinic 
acid  for  the  dietary  management  and  general  recommendations  for  the 
prevention  and  treatment  of  nutritional  deficiencies.  Single  vitamin  defi- 
ciencies occur  rarely,  and  despite  the  fact  that  riboflavin  deficiency  may 
dominate  the  clinical  picture,  it  is  unlikely  that  the  physician  will  see  a 
patient  who  has  uncomplicated  riboflavin  deficiency.  1  here  are  no  defi- 

VOL.  I.  948 


45 2 ( II 2 )         VITAMINS  AND  VITAMIN  DEFICIENCY 

nite  lesions  which  are  pathognomonic  of  riboflavin  deficiency.  The 
cheilosis  or  the  ocular  manifestations  may  or  may  not  be  due  to  riboflavin 
deficiency.  The  authors  give  from  5  to  50  mgm.  of  riboflavin,  but  as  a 
rule,  they  find  that  10  mgm.  daily  is  adequate  for  the  average  case.  It 
may  be  given  orally,  intravenously  or  intramuscularly.    Subcutaneous 

FOODS    AS   SOURCES  OF 

RIBOFLAVIN 

(vitamin  g) 

Milk  is  the  most  important  common  source  of 
riboflavin.  This  vitamin  is  not  readily  destroyed 
by  heat  but  it  may  be  lost  by  extraction  in  water 
during  cooking  and  by  prolonged  exposure  to  light. 


CONTRIBUTION  OF  SELECTED  SERVINGS  OF  A  FEW  FOODS  AS 
PERCENTAGES  OF  ADULT  MALE  ALLOWANCE  (2.7  MILLIGRAMS) 

0             25°/.         50% 

75%          100% 

■ 

mg 
6mg 

DRIED  BREWER'S  YEAST     loz     ^H^M^  II 

MILK                        ipmt  ^m^^m  09 

PRUNES                                     I'^zoz   HHl    OUmg 
FISH                                       4.0Z    hm     040mg 

BEEF                                  4-oz    ^    029mg 

DRIED  BEANS  and  PEAS     Fzoz  kH     027m9 

PORK                                 4o2    m  0.u\mq 

SNAP  BEANS                    i'^ioz  M  022'mg 

ONE  EGG                          l^oz   m    0  20'mg 

CHICKEN                           4oz     m    0I7Jmg 

ENRICHED  BREAD           4oz     HOiemg 

SPINACH                                   i'^zoz    iOWmg 

CHEESE   (Cheddar)                 loz      I  Ollmg 

PEANUTS                                  loz       ■  Ollmg 

CAULIFLOWER                3'ioz    ■  Ollmg 

ilResejrch  Council 


Fig.  42.    Foods  as  sources  of  riboflavin  (Vitamin  G;. 

auiiiir.i^irr.iion  causes  considerable  pain.  The  symptoms  are  relieved 
much  more  quickly  by  parenteral  than  by  oral  therapy.  Cheilosis, 
corneal  ulceration,  corneal  vascularity,  photophobia  and  non-infectious 
conjunctivitis  respond  rapidly  to  treatment  with  riboflavin,  if  they  are 
due  to  a  deficiency  of  riboflavin.  The  tendency  of  lesions  to  reappear 
after  cessation  of  treatment  is  common  and  may  occur  even  when  the 
Vol.  I.  948 


RIBOFLAVIN:  TOXICITY  452(113) 

dietary  is  at  an  optimal  level.  Consequently  frequent  observation  is  nec- 
essary for  a  long  period  of  time.  Should  relapse  occur,  the  reinstatement 
of  therapy  usually  affords  prompt  amelioration  of  the  symptoms.  The 
authors  wish  to  stress,  however,  that  neither  the  cheilosis  nor  the  dilated 
blood  vessels  of  the  eye  are  pathognomonic  of  riboflavin  deficiency. 
They  may  arise  from  other  causes  in  which  case  riboflavin  will  not  cor- 
rect them. 

Toxicity 

Riboflavin  is  practically  non-toxic.  Mice  fed  over  5,000  times  the 
daily  requirement  do  not  show  any  pathological  symptoms.  The  authors 
have  given  100  mgm.  daily  for  three  months  to  patients  without  any  ill 
effects  resulting. 


Vol.  I.  948 


452(114)         VITAiMINS  AND  VITAiVIIN  DEFICIENCY 

FOLIC  ACID 
History 

The  finding  of  a  synthetic  chemical  compound  of  known  molecular 
structure,  which  is  effective  in  treating  persons  with  nutritional  macro- 
cytic anemia,  pernicious  anemia  and  the  macrocytic  anemia  of  sprue  is  a 
medical  event  of  great  importance.  This  substance,  commonly  called 
"folic  acid",  is  the  newest  member  of  the  vitamin  B  complex.  The  name 
folic  acid  originally  was  given  to  a  mixture  of  substances  obtained  in 
nearly  pure  form  from  spinach  by  Mitchell,  Snell  and  Williams^^\  Their 
concentrate  was  shown  to  support  growth  for  two  organisms  frequently 
used  in  microbiological  investigations,  Lactobacillus  casei  and  Strepto- 
coccus faecalis.  Strictly  speaking,  the  Lactobacillus  casei  factor,  or 
pteroylglutamic  acid  as  it  properly  is  termed  chemically,  should  not  be 
called  folic  acid.  The  term  has  become  so  widely  used,  however,  that 
it  will  be  regarded  as  synonmous  with  the  Lactobacillus  casei  factor  or 
pteroylglutamic  acid. 

This  substance  gradually  emerged  as  a  separate  entity  as  the  result  of 
the  work  of  many  investigators  in  many  laboratories  over  a  period  of 
eight  years.  In  1938  Stokstad  and  Manning-^"  reported  that  a  purified 
diet,  even  when  supplemented  with  crude  concentrates  containing  thia- 
mine, riboflavin,  niacin,  pyridoxine  and  pantothenic  acid,  would  not 
satisfy  the  nutritional  requirements  of  chicks,  but  that  the  missing  factor 
was  supplied  by  the  addition  of  concentrates  from  yeast  and  alfalfa-^^ 
In  1940  Hogan  and  Parrott"'^  reported  that  an  anemia  developed  in 
chicks  on  a  purified  diet,  unless  they  were  given  an  unidentified  factor, 
which  could  be  supplied  with  suitable  preparations  obtained  from  liver. 
The  same  year  Snell  and  Peterson-^^  showed  that  an  unidentified  water- 
soluble  factor,  "the  yeast  norite  eluate  factor",  was  necessary  for  the 
growth  of  L.  casei.  Later  Hutchings  and  his  associates-^"  observed  that, 
when  the  factor  was  concentrated  from  extracts  prepared  from  liver, 
the  potency  in  promoting  the  growth  of  chicks  on  a  purified  diet  was 
found  to  increase  simultaneously  with  the  potency  as  measured  by  L. 
casei  factor.  This  proved  to  be  similar  to  the  "folic  acid"  obtained  from 
spinach  by  Mitchell,  Snell  and  Williams.  Minute  quantities  of  the 
L.  casei  factor  were  obtained  in  crystalline  form  from  liver  by  Pfiffner 
and  his  associates-'^  and  from  liver  and  yeast  by  Stokstad-'^  In  1945  it 
was  synthesized  by  Angier  and  his  co-workers^'"  and  a  few  months  later 
they  pubHshed  its  structural  formula  (see  Fig.  43)''^".  A  review  of  many 

Vol.  I.  948 


FOLIC  ACID:  CHEMISTRY  AND  PHYSIOLOGY    452(11.0 

aspects  of  the  studies,  which  led  to  the  isolation  and  synthesis  of  folic 
acid  and  studies  on  its  clinical  use,  has  been  published  recently  by  Berry 
and  Spies-"  and  by  Spies^«^ 

Chemistry  and  Physiology 

As  can  be  seen  from  the  formula  (Fig.  43),  folic  acid  contains  a 
pteridine  ring  and  one  molecule  each  of  para-aminobenzoic  acid  and 


COOM 

I 


HOOC-CHi-CHj-CH-NH-C  — ^]3~  NH-CH, 


A  A 


Ynh, 


OH 


N-C4-{K2-Qmlno-4-hydroxy-6-p+eridyl) methyl]  omino)  benzoyl]  glutamic    acid 
Fig.  43.    Structural  formula  of  the  liver  L.  casei  factor 

glutamic  acid.  Pteroic  acid  and  glutamic  acid  are  of  great  interest  be- 
cause of  their  chemical  relationship  to  the  folic  acid  molecule.  As  can 
be  seen  from  their  chemical  formula  in  Figs.  44  and  45,  pteroic  acid 
differs  from  folic  acid,  pteroylglutamic  acid,  by  the  absence  of  one 
molecule  of  glutamic  acid.  In  their  studies  on  the  synthesis  of  folic  acid 
Angier  and  his  associates  found  that  by  substituting  p-aminobenzoic  acid 


HOOC 


\_NH-CH. 


NHj 


Oh 


Fig.  44.     Structural   formula   of   petroic   acid. 


for  p-aminobenzoyl-i  (+) -glutamic  acid  in  the  process  a  compound  was 
produced  which  had  growth  activity  for  Streptococcus  faecalis  but  not 
for  L.  casei  and  the  chick.  The  term  assigned  to  this  compound  is  pteroic 
acid.  In  contrast  to  pteroylglutamic  acid,  which  is  a  potent  hemopoietic 
agent,  pteroic  acid  and  glutamic  acid  do  not  show  any  hemopoietic  ac- 
tivity when  administered  either  separately  or  together.  It  must  be 
assumed,  therefore,  that  these  substances  must  be  prefabricated  to  form 
Vol.  I.  948 


452(116)         VITAiMINS  AND  VITAMIN  DEFICIENCY 

pteroyl^lutamic  acid  before  they  can  be  utilized  by  the  body  for  blood 
regeneration. 

"  FoHc  acid  is  a  bright  yellow  substance  which  crystallizes  as  is  shown 
in  Fi^.  46.  It  is  destroyed  fairly  rapidly  by  heating  with  dilute  mineral 
acids"  and  sunliirht  has  a  destructive  effect  on  a  solution  of  folic  acid.  It 
occurs  in  nature  in  a  free  form  and  also  as  a  part  of  various  complexes. 
The  following  substances  have  been  isolated  in  crystalline  form;  (i) 
vitamin  Be,  (2)  Lactobacillus  casei  factor  from  liver,  (3)  Lactobacillus 

COOH 
I 

CH2 

I 
CHa 

HC  — NHa 
COOH 

Fig.  45.     Srrucrunil   formula   of  glutamic   acid. 

casei  factor  from  yeast,  (4)  another  Lactobacillus  casei  factor  isolated 
from  a  fermentation  residue  and  (5)  vitamin  Br.  conjugate.  \"itamin  Be, 
the  L.  casei  factor  from  liver  and  the  L.  casei  factor  from  veast  are  iden- 
tical with  the  synthetic  product  described  by  Angier  and  his  associates. 
This  compound,  folic  acid  or  pteroylglutamic  acid,  contains  one  mole- 
cule of  glutamic  acid.  In  contrast,  the  conjugated  L.  casei  factor  isolated 
from  the  fermentation  residue  yields  three  molecules  of  glutamic  acid 
and  is  called  pteroyltriglutamic  acid.  The  vitamin  Be  conjugate  contains 
7  molecules  of  glutamic  acid  and  is  termed  pteroylheptaglutamic  acid. 
The  structural  formulas  of  these  substances  could  be  written  as  is  shown 
in  Fig.  47,  although  the  precise  structure  is  not  known  at  this  time.  These 
substances  are  somew^hat  effective  in  producing  a  hemopoietic  response 
in  certain  types  of  macrocytic  anemia  in  relapse  but  less  effective  per 
Vol.  I.  948 


FOLIC  ACID:  CHEMISTRY  AND  PHYSIOLOGY    452(1 17) 

unit  of  weight  than  is  folic  acid"''^  Within  24  hours  after  the  administra- 
tion of  pteroylglutaniic  acid  to  persons  with  pernicious  anemia  there  is 
a  great  increase  in  the  urinary  excretion  of  this  substance,  whereas  the 
administration  of  vitamin  Be  conjugate  is  not  followed  by  a  great  increase 
in  the  amount  of  folic  acid  excreted  in  the  urine  of  some  patients  with 
pernicious  anemia  (Fig.  48). 

Whether  or  not  most  animals  can  synthesize  folic  acid  has  not  been 
determined.  The  relative  scarcity  of  it  in  animal  tissues  suggests  that,  if 


r        >   i/"--   ^ 

• 

«#-^     ^  9F 

^    A.       '\ 

jiAr 

")!  ■ 

«           i 

« 

1^' 

r 

I 

^    ■ 

-  >•»  ■ 

/  ^^ 

Iv       W^ 

J*  •  >-      ...      -   V-  ,,. 

*  ^  ♦ 

X 

^     Pi 

i^  "/ 

&^.            ^    ■-" 

#"  ■ 

^  «^ 

■  ^i>  -./  ^  '  :^ 

i                  ^  ^'       ..                          .         1 

Fig.  46.     Microphotograph    showing    crystalline    folic    acid     (courtesy    of    Ledcrle 
Laboratories,  Inc.). 

it  is  synthesized,  only  small  quantities  of  it  are  produced  or  only  small 
amounts  are  stored.  It  is  possible  that  the  bacteria  normally  present  in 
the  intestinal  tract  of  some  animals,  such  as  the  rat,  may  synthesize  con- 
siderable quantities.  Experimentally  folic  acid  has  been  found  to  be 
essential  for  the  proper  nutrition  of  a  variety  of  micro-organisms  and 
laboratory  animals  either  as  a  growth-promoting  or  a  hemopoietic- 
stimulating  factor  or  both"^^-"".  Although  its  role  in  human  nutrition 
is  not  clear,  its  effectiveness  in  the  treatment  of  macrocytic  anemias  in 
relapse  has  been  established. 

Pteroylglutamic  acid  is  distributed  widely  in  both  plant  and  animal 

Vol.  i.  948 


452(1 18)         VITAMINS  AND  VITAMIN  DEFICIENCY 

tissues.  At  the  present  time  the  distribution  of  folic  acid  in  foods  usually 
is  studied  by  microbiological  assays.  Olson,  Burris  and  Elvehjem'"'  have 
classified  foods  assayed  for  their  folic  acid  content  by  such  methods  as 
follows: 

I.    ^"ery  high  in  folic  acid  content:  deep  green  leafy  vegetables,  liver 


C„-„H-c"-(^^r.H-CH.4^  Jl^^, 


LIVES  L.  CASEI    FACTOR 

(PTEOOVL    GLUTAMIC  ACID) 


COOH  CH, 

CM-NH-C-CHt 

I 

COOH  CHt 

CH-NH-C-CHi 
I 
CM, 

I  CPTEBOYL     Dl  -  G 

CH. 

I 
COOH 


FERMENTATION     L.    CASEI     FACTOR 

/L     GLUTAMIC     ACID> 


COOH     „CH, 
I  II   I 

CH-NH-C-CHj 


COOH       _CH, 
I  l?\ 

CH-NH-C-CH 
I 
COOH      oCHt 

'  Jl  i. 

CH-NH-C-CH. 

I 


VITAMIN     be    CONJUGATE 

(PTEOOVL   HEXA-GLUTAMVL  GLUTAMIC    ACID) 


COOH  CH, 
I  //  I 

CH-MH-C-CH, 
I 

CH, 

CH, 
I 
COOH 


COOH        CH, 

I  '?\ 

CH-NH-C-CH, 


Fig.  47.     Suggested  structural  formulae  for  fermentation  L.  casei  factor  and  vitamin 
Bo    conjugate. 


2.  High  in  folic  acid  content:  fresh  orecn  vegetables,  cauliflower  and 

kidney 

3.  Medium  in  folic  acid  content:  beef,  veal,  dry  breakfast  cereals 

from  wheat 

4.  Low  in  folic  acid  content:  root  vegetables,  tomatoes,  cucumbers, 

light  green  leafy  vegetables,  bananas,  pork,  ham,  lamb,  cheese, 
milk,    dry   cereals   prepared    from    rice   or   corn    and   many 
canned  foods 
Vol.  I.  948 


FOLIC  ACID:  PATHOLOGICAL  PHYSIOLOGY    452(119) 

Path(h.o(;ical  Physiology 

Folic  acid  has  a  profound  effect  on  the  bone  marrow  of  persons  with 
certain  types  of  macrocytic  anemia  in  relapse.    Nevertheless,  it  cannot 

T.D     NUTRITIONAL     MACROCYTIC     ANBMIA. 

urinahy  excretion  of    l.  casei   factor. 


k 

ij 
X 
'^ 

0 


0* 

<^ 
0 
0 
<^ 
0 


4     5    6     7    6     9    <0 


It    12    13    14   IS    16    17   16    19   20  11    "   '3    M    ''*  '* 
OCTOBCH 

DAYS 


IS  M  17  1%  W  30  1 


Fig.  48.     Chart  showing  excretion  in  the  urine  of  foHc  acid  after  giving  to  a  pa- 
tient with  nutritional  macrocytic  anemia  5  c.c.  of  vitamin  Be  conjugate  daily  for  9  days. 

be  said  that  the  megaloblastic  arrest  of  the  bone  marrow  was  caused  by 
a  folic  acid  deficiency.   Liver  extract  and  ventriculin  produce  a  similar 
Vol.  L  948 


452(i2o)         VITAMINS  AND  VITAMIN  DEFICIENCY 

therapeutic  effect,  yet  there  is  much  reason  to  believe  that  fohc  acid  is 
different  from  the  anti-anemic  factor  or  factors  in  these  substances. 

By  using  the  sternal  puncture  in  patients  under  investigation,  it  is 
possible  to  follow  the  action  of  folic  acid  step  by  step  in  the  bone  mar- 
row. In  contrast  to  the  peripheral  blood  picture,  where  changes  first 
become  appreciable  several  days  after  the  onset  of  treatment,  profound 
transformations  of  the  bone  marrow  occur  earlier.  Reticulocytosis  can 
be  detected  in  the  bone  marrow,  sometimes  as  early  as  the  second  day. 
The  number  of  megaloblasts  and  early  erythroblasts  decreases  progres- 
sively, and  the  late  erythroblasts  and  normoblasts  increase.  Eventually 
the  normal  ratio  of  nucleated  red  blood  cells  and  white  blood  cells  of 
the  marrow  is  re-established.  In  the  following  series  of  studies  done  at 
the  time  the  patient  was  admitted  to  the  hospital  and  twice  during 
therapy  one  sees  a  disappearance  of  the  megaloblastic  arrest,  and  the  bone 
marrow  becomes  normal. 

Bone  marrow  study  on  admission 

Sternal  bone  marrow  was  obtained  i)v  means  of  the  Turkel 
trephine; 
200  ^^^B.C.  were  counted. 


\'()i 


Cells 

Nwiiher 

Percent 

PMN 

120 

60 

Metamyelocytes 

56 

28 

C  myelocytes 

2 

I 

B  myelocytes 

0 

0 

A  myelocytes 

0 

0 

Basophils 

2 

I 

Basophilic  myelocytes 

0 

0 

Eosinophils 

4 

2 

Eosinophilic  myelocytes 

10 

5 

Plasma  cells 

2 

I 

jVIegakaryocytes 

0 

0 

Primitive  cells 

4 

2 

Total 

200 

100 

Megaloblasts 

12 

Early  erythroblasts 

6 

Late  erythroblasts 

9 

Normoblasts 

15 

l\)tal 

42 

>i .  1.  948 

FOLIC  ACID:  PATHOLOGICAL  PHYSIOLOGY    452(121) 

Impression:    Hyperplastic  bone  m;irroM-  ^\  irh  megaloblastic  arrest. 

arrest. 
Bone  marrow  study  made  on  the  51st  da\-  of  treatment  showed: 


Cells 

Nii'inher 

Percent 

PiMN 

S6 

43.0 

Metamyelocytes 

5" 

25.0 

C  myelocytes 

B  myelocytes 

A  myelocytes 

Basophils 

Basophilic  myelocytes 

Eosinophils 

Eosinophilic  myelocytes 

Plasma  cells 

3 
4 

5 

I 

I 

9 

35 

2 

1-5 
2.0 

2-5 

0.5 
0.5 

4-5 

17-5 
1 .0 

A/Iegakaryocytes 
Primitive  cells 

I 

0.5 

1-5 

Total 

200 

100 

A^egaloblasts 
Early  erythroblasts 

6 
1 1 

Late  erythroblasts 

20 

Normoblasts 

109 

Total 

146 

Impression:    A  reactive  bone  marrow  which  shows  a  good  re- 
sponse to  therapy.    There  is  still  some  evidence  of  megalo- 
blastic arrest. 
Bone  marrow  study  made  on  the  74th  day  of  treatment  showed: 


PAIN 

94 

47.0 

Metamyelocytes 

54 

27.0 

C  myelocytes 

8 

4.0 

B  myelocytes 

5 

2-5 

A  myelocytes 

2 

I.O 

Basophilic  myelocytes 

I 

•5 

Eosinophils 

6 

3.0 

Eosinophilic  myelocytes 

17 

8.5 

Plasma 

I 

•5 

Megakaryocytes 

I 

•5 

Primitive 

6 

3.0 

Lymphocytes 

5 

2-5 

Total 

200 

100 

\\)L.  I.  948 

452(122)         V1TAA1INS  AND  VITAMIN  DEFICIENCY 


Cells 
Alegaloblasts 
Early  erythroblasts 
Late  erythroblasts 
Normoblasts 

Total 


Number 
o 
3 
24 

37 

64 


Percent 


Impression:  Essentially  normal  marrow  except  for  an  increased 
number  of  eosinophilic  elements.  There  has  been  a  definite 
change  toward  normal  since  the  51st  day  of  treatment. 

CAS£    OF   P£fiN/C/OUS   ANEM/A    -    /"Ol/C  AC/O    r/iffiAPV 


fOL  /C    A  C/D      !0  Mg.   ora//y   q.  c/ 


/ler 

nog/Ob  in 

/ 

h 

/ 

l\ 

r'\ 

1 

A    /-'-\    >./\'     A-'/° 


/    V^/      ,/---/  V--N 


/  \     /  ''•/ 


Red  B/ood  Cells 


29    30   31     32    J3    J4    35    36    3'    Sa  39    lO  <l    <2   «3 


Fig.  49.     Chart  showing  clianges  in  hemoglobin,  red   blood   cells  and   reticulocytes 
in  patient  with  pernicious  anemia  following  oral  administration  of  folic  acid. 

Reticulocytosis  in  the  peripheral  blood  frequently  is  detected  from 
about  the  third  to  the  fifth  day  of  therapy.  A  peak  is  reached  on  the 
sixth  to  the  tenth  day.  The  height  of  the  rise  varies  from  case  to  case 
depending  upon  the  severity  of  the  anemia,  the  adequacy  of  the  dose  of 
folic  acid  and  the  presence  or  absence  of  complications.  In  addition  to 
the  reticulocytosis  there  is  a  gradual  increase  in  the  number  of  red  blood 
cells  and  in  the  hemoglobin  (Fig.  49).  The  thrombocytopenia  and  leu- 
kopenia, which  so  often  are  associated  with  macrocytic  anemia,  frc- 

VOL.  1.  948 


FOLIC  ACID:   DIAGNOSIS  452(123) 

quently  are  corrected  by  folic  acid.  The  blood  regeneration,  which 
follows  folic  acid  therapy,  is  comparable  to  that  which  follows  therapy 
with  reticulogen,  concentrated  liver  extract.  Thymine  (5-methyl  uracil), 
another  anti-anemic  substance,  likewise  produces  blood  regeneration"'", 
but  the  response  is  of  a  lower  order  than  that  which  follows  a  potent 
liver  extract  or  folic  acid  as  can  be  seen  in  Fig.  50.  Furthermore  the  large 
amount  of  thymine  necessary  to  produce  a  therapeutic  response,  up  to  1 5 
grams  daily,  makes  it  impractical  as  a  therapeutic  substance,  although  it 
is  of  great  scientific  interest. 

Symptomatology 

Since  it  is  not  known  that  such  a  thing  as  a  specific  deficiency  of  folic 
acid  exists  in  human  beings,  the  symptomatology  of  a  folic  acid  defi- 
ciency in  man  cannot  be  described.  Nevertheles  sthe  judicious  adminis- 
tration of  folic  acid  in  suitable  amounts  is  effective  in  treating  Addisonian 
pernicious  anemia,  nutritional  macrocytic  anemia  and  the  macrocytic 
anemia  of  pellagra,  pregnancy  and  sprue.  Some  of  the  more  pertinent 
findings  are  discussed  under  Diagnosis  and  Treatment. 

Diagnosis 

Although  the  effectiveness  of  folic  acid  as  a  therapeutic  agent  in 
treating  Addisonian  pernicious  anemia,  nutritional  macrocytic  anemia 
and  the  macrocytic  anemia  of  pellagra,  pregnancy  and  sprue  has  been 
established"'^*'"'''-"^  it  cannot  be  overstressed  that  it  is  of  no  value  in  treat- 
ing leukemia,  aplastic  anemia  or  iron  deficiency  anemia.  The  anemia 
associated  with  liver  disease  usually  does  not  respond  to  folic  acid,  but 
in  some  cases  it  does.  Nutritional  leukopenia  improves  following  treat- 
ment with  folic  acid,  but  other  types  of  leukopenia  are  not  relieved.  The 
physician,  who  would  prescribe  folic  acid,  should  first  make  an  accurate 
diagnosis. 

The  clinical  syndromes  of  Addisonian  pernicious  anemia,  nutritional 
macrocytic  anemia,  tropical  sprue  and  the  macrocytic  anemia  of  pellagra 
and  pregnancy  are  indistinguishable  either  from  examination  of  the 
peripheral  blood  or  from  bone  marrow  studies.  A  characteristic  feature 
of  pernicious  anemia  is  the  absence  of  free  hydrochloric  acid  in  the 
gastric  juice  even  after  histamine  stimulation.  Many  investigators  agree 
that  so-called  tropical  and  non-tropical  sprue  are  essentially  the  same 

Vol.  I.  948 


452(124)         VITAMINS  AND  VITAMIN  DEFICIENCY 


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Vol.  I.  948 


FOLIC  ACID:  TREATMENT  452(125) 

disease.  The  relationship  of  nutritional  macrocytic  anemia  and  sprue  is 
more  difficult  to  grasp.  Persons  \^'ith  either  disease  may  have  severe 
diarrhea,  but  the  characteristic  diarrhea  of  sprue  is  the  best  differentiating 
feature,  and  it  is  on  the  presence  of  this  type  of  diarrhea  that  the  diagnosis 
of  sprue  is  based.  In  sprue  the  stools  usually  vary  in  consistency  from 
liquid  to  semi-solid  and  in  color  from  whitish  yellow  to  yellowish  green, 
while  in  nutritional  macrocytic  anemia  rarely  are  they  foamy,  but  they 
are  foul  in  odor.  Bowel  movements  in  sprue  may  occur  from  3  to  20  or 
even  30  times  a  day,  tending  to  occur  immediately  after  the  patient  eats 
food  of  any  kind,  and  the  volume  of  the  feces  in  24  hours  is  greatly  in 
excess  of  the  normal  volume.  Acid  steatorrhea,  which  almost  invariably 
is  present  in  sprue,  does  not  occur  in  nutritional  macrocytic  anemia.  The 
weight  loss  in  sprue  may  be  greater  and  less  gradual  than  that  which 
accompanies  nutritional  macrocytic  anemia. 

Even  when  a  considerable  number  of  eminently  qualified  physicians 
examine  a  large  group  of  patients  with  anemia,  a  specific  diagnosis  is  apt 
to  be  made  in  some  cases,  whereas  in  others  opinion  is  divided.  Fre- 
quently the  physician  may  make  a  diagnosis  the  first  time  he  examines 
the  patient  and  observes  him  throughout  a  relapse  of  the  disease,  but 
during  a  later  recurrence  he  may  change  the  diagnosis.  The  author  con- 
siders that  the  essential  feature  of  the  anemias,  which  can  be  expected  to 
respond  to  folic  acid  therapy,  is  megaloblastic  arrest  of  the  bone  marrow 
associated  with  macrocytic  anemia  in  persons  who  appear  to  have  Addi- 
sonian pernicious  anemia,  sprue,  nutritional  macrocytic  anemia  or  the 
macrocytic  anemia  of  pellagra  or  pregnancy. 

When  the  physician  realizes  that  patients  with  various  clinical  condi- 
tions respond  to  folic  acid  therapy,  it  might  seem  academic  to  stress  the 
necessity  of  making  a  specific  diagnosis.  The  prognosis  and  duration  of 
therapy  vary  so  greatly  in  the  different  types  of  macrocytic  anemia, 
however,  that  no  effort  should  be  spared  in  obtaining  as  much  precise 
and  pertinent  information  as  possible.  The  finding  of  the  specific  effect 
of  the  folic  acid  molecule  on  the  cells  of  the  bone  marrow  and  perhaps, 
on  other  cells  opens  up  a  fresh  and  fertile  field  for  the  clinical  inves- 
tigator who  must  now  re-define  the  macrocytic  anemias  in  the  light  of 
all  the  various  loose  threads  which  enter  into  the  meshwork  of  their 
pathogenesis. 

Treatment 

As  yet  no  satisfactory  explanation  has  been  given  for  the  fact  that 
relatively  large  amounts  of  folic  acid  are  required  to  produce  a  satisfac- 

\^OL.  I.  948 


452(126)         VITAMINS  AND  VITAMIN  DEFICIENCY 


tory  hemopoietic  response.   Despite  the  many  intensive  cHnical  studies, 
which  have  been  made  on  f oUc  acid  as  a  therapeutic  agent,  the  last  word 

RESPONSE   OF   A    CAS£    OF     SPRUf     TO     FOL/C    AC/D 


r 


f=Oi./C 

AC/O 

JO   mg. 

oro//y     g  d. 

« 

i 

5  O. 

^ 

J  5. 

^___^ 

■ -—.- 

-" ■ • 

y' 

1  O. 

/"■""'^^ 

-^ 

O  5. 

^ 

y^-^ 

9  0. 

J 

1  a 

^^\/ 

Fig.  51.     Response  of  a  patient  \\ith  sprue  to  administration  of   folic   acid. 
Vol.  1.  948 


FOLIC  ACI D :  TREATMENT  45 ^  ( >  ^ 7 ) 

on  dosage  cannot  be  stated  definitely,   in  most  cases  from  lo  to  20  mgm. 
daily  in  divided  doses,  given  either  orally  or  parenterally,  is  sufficient  to 


Fig.  52.    X-ray  showing  intestinal  pattern  in  sprue  before  treatment. 

induce  a  remission  in  persons  with  nutritional  macrocytic  anemia,  the 
macrocytic  anemia  of  pregnancy,  pellagra,  sprue  and  Addisonian  per- 
nicious anemia. 

The  dramatic  response  of  the  hone  marrow  and  peripheral  blood 

Vol..  I.  948 


452(128)         VITAMINS  AND  VITAMIN  DEFICIENCY 

to  folic  acid  in  properly  selected  patients  with  macrocytic  anemia  in 
relapse  is  discussed  and  illustrated  under  Fathological  Physiology.   The 


Fig.  53.    X-ray  showing  intestinal  pattern  of  same  patient  with  sprue  as  shown  in 
Fig.  52  before  treatment. 

clinical  response  is  equally  dramatic.  At  the  time  reticulocytosis  begins 
the  patients  state  voluntarily  that  they  feel  stronger.   Those  who  have 
lost  their  appetites  experience  a  great  increase  in  the  desire  for  food,  and 
Vol.  I.  948 


FOLIC  ACID:  TREATMENT 


452(129) 


in  nvanv  cases  the  food  intake  increases  from  less  than  i  ,000  calories  daily 
to  between  3,000  and  4,000  calories  within  a  day  or  two  from  the  time 
reticLilocytosis  begins.    In  cases  of  extreme  weight  loss,  such  as  that 


Fig.  54.    X-ray  showing  intestinal  pattern  of  same  patient  with  sprue  as  shown  in 
Figs.  52  and  53  before  treatment. 

which  occurs  in  sprue,  the  gain  in  appetite  and  weight  is  particularly 
remarkable  as  can  be  seen  in  Fig.  51.   No  adequate  explanation  can  be 
given  for  the  prompt  improvement  in  the  diarrhea  in  nutritional  macro- 
Voi-  I.  948 


452(130)         MTAMINS  AND  VITAMIN  DEFICIENCY 

cytic  anemia.  The  stools  may  tend  to  become  normal  in  frequency,  color 
and  volume. 

Folic  acid  therapy  has  a  striking  effect  on  the  gastrointestinal  tract 


Fig.  55.    X-ray  of  same  patient  with  sprue  as  shown  in  Figs.  52,  53  and  54  six  weeks 
after  treatment  with  folic  acid  showing  return  to  normal  of  intestinal  pattern. 

of  persons  with  tropical  sprue-^^  as  can  be  seen  in  the  illustrations  Figs. 
5-'  53'  54'  55  ^^1  made  on  the  same  patient.  The  first  three  are  taken 
before  therapy  and  the  fourth  six  weeks  after  folic  acid  therapy  was 
initiated.  The  abnormal  dilatations  and  spasms  seen  in  Figs.  52,  53  and 
Vol.  I.  948 


FOLIC  ACID:  TREATMENT 


452(130 


PERCENT        0     10    20    30  40    50    60   70    80    90    100 

PROTEIN 

CALORIES 

CALCIUM 

IRON 

VITAMIN   A 

THIAMINE 

ASCORBIC   ACID 

RIBOFLAVIN 

NIACIN 

PERCENT        0     10    20    30  40    50    60   70   80   90    100 
HHl   RECOMMENDED    ALLOWANCES   OF  NUTRIENTS 

liiiiiiiiii:!  nutrients  supplied  by  diet  of  patient 

*  RECOMMENDED  BY  COUNCIL  ON   FOODS  AND  NUTRIT10N_,  NATIONAL  RESEARCH   COUNCIL 

Fig.  56.     Chart  showing  nutrients  supplied  by  diet  of  patient  with  chronic  pellagra 
and  nutritional  macryocytic  anemia  contrasted  to  recommended  allowances  of  nutrients. 


Vol.  L  948 


452(132)         VITAMINS  AND  MTAMIN  DEFICIENCY 

54  disappeared  as  can  be  seen  in  Fig.  S5^  which  shoAvs  that  the  barium 
column  is  continuous  and  appears  perfectly  normal. 

The  chief  limitation  of  folic  acid  as  a  therapeutic  agent  is  that  it  will 
neither  prevent  the  development  of  acute  or  subacute  combined  system 
disease  nor  relieve  it  once  it  has  developed"*^^"'".  Liver  extract  along  with 
folic  acid  should  be  given  in  a  dosage  sufficient  to  relieve  signs  of  acute 
or  subacute  degeneraton  of  the  spinal  cord.  In  patients,  who  are  allergic 
to  liver  extract,  folic  acid  is  a  valuable  substitute  unless  the  patient  has 
neural  degeneration.  In  such  cases  folic  acid  therapy  should  be  supple- 
mented with  the  necesarv  amount  of  liver  extract  to  bring  steps  to  over- 
come the  allergic  action  of  the  liver  extract. 

In  the  treatment  of  macrocytic  anemia  correct  diagnosis  is  basic.  The 
objective  in  the  treatment  of  every  patient  is  the  restitution  of  the  red 
blood  cells,  the  white  blood  cells,  the  platelets  and  the  hemoglobin,  the 
reduction  of  the  red  blood  cells  to  normal  size  and  the  relief  of  all  his 
symptoms  with  the  result  that  he  becomes  completely  rehabilitated.  In 
order  to  realize  this  objective  it  is  necessary  to  make  a  thorough  study 
of  the  patient  and  of  his  blood  findings.  Once  the  diagnosis  is  made,  he 
should  be  given  general  therapeutic  measures  which  will  promote 
physical  rest  and  mental  serenity.  A  proper  diet  should  be  stressed 
throughout  the  whole  period  of  his  convalescence  and  thereafter  for 
the  remainder  of  his  life.  He  should  be  treated  with  physiotherapy  for 
any  disturbances  of  gait  and  locomotion.  Tranfusion  should  be  given,  if 
necessary,  to  save  life.  Co-existing  diseases  should  be  treated,  and  every 
effort  should  be  made  to  eradicate  them.  During  convalescence  the 
physician  must  remind  patients  with  anemia  to  avoid  unnecessary  fa- 
tigue, since  many  of  them  are  old,  and  their  heart  function  is  impaired. 
Dramatic  recovery  can  be  expected,  when  folic  acid  is  given  promptly, 
efficiently  and  adequately  to  properly  selected  patients. 

Despite  the  fact  that  the  blood  levels  improve  following  folic  acid 
therapy,  the  general  nutritional  status  of  the  patient  frequently  warrants 
particular  attention.  The  patient  in  severe  relapse  rarely  is  interested 
in  food,  and  it  is  unlikely  that  he  has  been  consuming  an  adequate  diet 
(See  Fig.  ^6).  As  a  rule,  the  appetite  increases  tremendously  after  re- 
mission begins,  and  it  is  not  unusual  for  him  to  consume  large  amounts 
of  food.  At  this  period  it  is  of  utmost  importance  to  instruct  every 
patient  in  regard  to  a  proper  diet.  Experience  has  taught  us  that  there  is 
a  great  variation  in  the  individual  needs  of  different  patients.  The  patient 
with  sprue  or  pellagra  usually  is  considerable  underweight  and  has  a 
deficiency  of  many  nutrients.   Accordingly  he  may  need  a  diet  that  is 

Vol.  T.  948 


BIBLIOGRAPHY  452(133) 

not  only  high  in  calories  but  is  rich  in  all  the  essential  nutrients.  In 
contrast,  some  persons  with  pernicious  anemia  are  obese,  and  the  caloric 
intake  can  be  restricted  without  impairing  the  diet  in  respect  to  other 
nutrients.  Some  patients  may  have  renal  insufficiency,  diabetes  or  other 
diseases  which  require  special  dietary  control.  In  such  cases  the  diet 
should  be  prescribed  for  the  individual  patient  and  planned  with  great 
care.  In  some  cases  macrocytic  anemia  is  accompanied  bv  hypochromic 
anemia  (iron  deficiency  anemia).  Folic  acid  naturally  will  not  replenish 
the  deficiency  of  iron,  and  in  such  cases  optimal  doses  of  iron  should  be 
given. 

Toxicity 

Apparently  large  amounts  of  folic  acid  can  be  given  with  impunity 
since  one  of  the  authors  (T.D.S.)  has  administered  400  mgm.  daily  for 
3  months  without  the  patient's  developing  untoward  symptoms. 


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244.  ELLENBERG,  M.  and  POLLACK,  H.:    Psuedo  ariboflavinosis.  Jour. 

Am.  Med.  Assoc,  1942,  CXIX,  790. 

245.  MANN,  A.  W.,  iMANN,  J.  M.  and  SPIES,  T.  D.:    A  clinical  study 

of  malnourished  edentulous  patients.  Jour.  Am.  Dent.  Assoc,  1945, 
XXXII,  13,-7. 

246.  SPIES,  T.  D.'  BEAN,  W.  B.  and  ASHE,  W.  F.:    Recent  advances  in 

the  treatment  of  pellagra  and  associated  deficiencies,  Ann.  Int.  Med., 
1939,  XII,  1830. 

247.  SPIES,  T.  D..  METER.  R.  W.  and  ASHE,  W.  F.:    Pellagra,  beriberi, 

and  riboflavin  deficienc\'  in  human  beings,  diagnosis  and  treatment. 
Jour.  Am.  Med.  Assoc,  1939,  CXIII,  931. 
Vol.  I.  948 


452(150)         VITAMINS  AND  VITAMIN  DEFICIENCY 

248.  KRUSE,  H.  D.,  SYNDENSTRIKER,  V.  P.,  SEBRELL,  W.  H.  and 

CLECKLEY,  H.  M.:  Ocular  manifestations  of  ariboflavinosis,  Pub. 
Health  Rep.  1940,  LV,  157. 

249.  SPIES,  T.  D.,  PERRY,  D.  J,  COGSWELL,  R.  C.  and  FROM- 

MEYER,  W.  B,:  Ocular  disturbances  in  riboflavin  deficiency,  Jour. 
Lab.  and  Clin.  Med.,  1945,  XXX,  751. 

250.  SEBRELL,  W.  H.:    Human  riboflavin  deficiency  in  The  Biological 

Action  of  the  Vitamins,  Ed.  by  E.  A.  Evans,  Jr.,  Univ.  Chicago 
Press,  Chicago,  1942. 

Folic  Acid 

251.  MITCHELL,  H.  K.,  SNELL,  E.  E.  and  WILLIAMS,  R.  J.:   The  con- 

centration of  folic  acid,  Jour.  Am.  Chem.  Soc,  1941,  LXIII,  2284. 

252.  STOKSTAD,  E.  L.  R.  and  MANNING,  P.  D.  V.:    Evidence  of  a 

new  s^rowth  factor  required  by  chicks.  Jour.  Biol.  Chem.,  1938, 
CXXV,  687. 

253.  JUKES,  T.  H.  and  BABCOCK,  S.  H.  Jr.:    Experiments  with  a  factor 

promoting  growth  and  preventing  paralysis  in  chicks  on  a  simpli- 
fied diet.  Jour.  Biol.  Chem.,  1938,  CXXV,  169. 

254.  HOG  AN,  A.  G.  and  PARROTT,  E.  M.:    Anemia  in  chicks  caused 

by  a  vitamin  deficiency.  Jour.  Biol.  Chem.,  1940,  CXXXII,  507. 

255.  SNELL,  E.  E.  and  PETERSON,  W.  H.:   Growth  factors  for  bacteria. 

X.  Additional  factors  required  by  certain  lactic  acid  bacteria.  Jour. 
Bact.,  1940,  XXXIX,  273. 

256.  HUTCHINS,  B.  L.,  BOHONOS,  N.,  HEGSTED,  D.  M.,  ELVEH- 

JEM,  C.  A.  and  PETERSON,  W.  H.:  Relation  of  a  growth  factor 
required  by  Lactobacillus  casei  E  to  the  nutrition  of  the  chick.  Jour. 
Biol.  Chem.,  1941,  CXL,  681. 

257.  PIFFNER,  J.  J.,  BINKLEY,  S.  B.,  BLOOM,  E.  S.,  BROWN,  R.  A., 

BIRD,  O.  D.,  EMMETT,  A.  D.,  HOGAN,  A.  G.  and  O'DELL, 
B.  L.:  Isolation  of  the  anti-anemic  factor  (vitamin  Be)  in  crystalline 
form  from  liver.  Science,  1943,  XCVII,  404. 

258.  STOKSTAD,  E.  L.  R.:    Some  properties  of  growth  factor  for  Lacto- 

bacillus casei,  Jour.  Biol.  Chem.,  1943,  CXLIX,  573. 

259.  ANGIER,  R.  B.,  BOOTHE,  J.  H.,  HUTCHINGS,  B.  L.,  MOWAT, 

J.  H.,  SEMB,  J.,  STOKSTAD,  E.  L.  R.,  SUBBAROW,  Y.,  WAL- 
LER, C.  W.,  COSULICH,  D.  B.,  FARENBACH,  M.  J.,  HULT- 
QUIST,  M.  F.,  KUH,  E.,  NORTHEY,  E.  H.,  SEEGER,  D.  R., 
SICKELS,  J.  P.  and  SMITH,  J.  M.,  Jr.:  Synthesis  of  a  compound 
identical  with  L.  casei  factor  isolated  from  liver.  Science,  1945, 
CII,  227. 
Vol.  I.  948 


BIBLIOGRAPHY  452(i5  0 

^60  ANGER,  R.  B.,  BOOTHE,  I.  H.,  HUTCHINGS,  B.  L.,  MOW  AT, 
J.  H.,  SEMB,  J.,  STOKSf  AD,  E.  L.  R.,  SUBBAROW,  Y.,  WAL- 
LER, C.  W.,  COSULICH,  D.  B.,  FARENBACH,  M.  J.,  HULT- 
QUIST,  M.  E.,  KUH,  E.,  NORTHEY,  E.  H.,  SEEGER,  D.  R., 
SICKELS,  J.  P.  and  SMITH,  J.  M.,  Jr.:  The  structure  and  syn- 
thesis of  the  liver  L.  casei  factor.  Science,  1946,  CIII,  667. 

251.  BERRY,  L.  J.  and  SPIES,  T.  D.:  The  present  status  of  fohc  acid.  Jour. 
Hemat.,  1946,  I,  271. 

262.  SPIES,  TOAl  D.:   Experiences  with  Folic  Acid,  Year  Book  Publishers, 

Inc.,  Chica£To,  1947. 

263.  SPIES,  TO]\f  D.  and  STONE,  ROBERT,  E.:    Some  recent  experi- 

ences with  vitamins  and  vitamin  deficiencies.  South.  Med.  Jour., 
1947,  XL,  46. 

264.  OLSON,  OSCAR  E.,  BURRIS,  R.  H.  and  ELVEHJEM,  C.  A.:    A 

prelimnarv  report  of  the  "folic  acid"  content  of  certain  foods, 
Jour.  Am.  Diet.  Assoc,  1947,  XXIII,  200. 

265.  FROMAIEYER,  WALTER  B.,  Jr.    and  SPIES,  TOM  D.:    Relative 

clinical  and  hematologic  effects  of  concentrated  liver  extract,  syn- 
thetic folic  acid  and  synthetic  5-methyl  uracil  in  the  treatment  of 
macrocytic  anemia  in  relapse,  Am.  Jour.  Med.  Sci.,  1947,  CCXIII, 

135- 

266.  SPIES,  TOiM  D.:    Effect  of  folic  acid  on  persons  with  macrocytic 

anemia  in  relapse.  Jour.  Am.  Med.  Assoc,  1946,  CXXX,  474. 

267.  GARCIA  LOPEZ,  GUILLERMO,  SPIES,  TOM  D.,  MENENDEZ, 

JOSE  ARISTIDES  and  LOPEZ  TOCA,  RUBEN:  Folic  acid  in  the 
rehabilitation  of  persons  with  sprue,  Jour.  Am.  Med.  Assoc,  1946, 
CXXXII,  906. 

268.  SUAREZ,  RAA10N  M.,  SPIES,  TOM  D.  and  SUAREZ,  RAiMON 

M.,  JR.:  The  use  of  folic  acid  in  sprue,  Ann,  Int.  Med.,  1947,  XXVI, 
643. 

269.  HERNANDEZ  BEGUERIE,  R.  L.:    Roentgenologic  studies  on  the 

effect  of  synthetic  folic  acid  on  the  gastrointestinal  tract  of  patients 
with  tropical  sprue.  Am.  Jour.  Roentgenol,  and  Rad.  Therapy,  1946, 
LVI,  337. 

270.  SPIES,  TOM  D.  and  STONE,  ROBERT  E.:    Liver  extract,  folic  acid 

and  thyamine  in  pernicious  anemia  and  subacute  combined  degenera- 
tion. Lancet,  1947,  I,  174. 
September  i,  1948. 


\^CL.  I.  948 


CHAPTER  X  (CONTINUED) 

VITAiMINS    AND    VITAAIIN     DEFICIENCIES 
(CONTINUED) 

VITAMIN    B,2 

By  TOM  1).  SPIES 

Table  ok  Qjntents 

History         452(153) 

Biochemistry  and  Physiology 452('54) 

Pathological   Physiology 452(156) 

Symptomatology 452(15^) 

Diagnosis 45^(157) 

Prevention  and  Treatment 452('57) 

Toxicity 452('6o) 

Bibliography 452(161) 

History 

The  modern  era  in  the  search  for  vitamin  Bij  and  suhst-.mces  that  act 
similarly  was  initiated  when  Minot  and  Murphy'"  noted  rapid  improve- 
ment on  feeding  liver  intensively  to  patients  with  pernicious  anemia. 
It  became  evident  that  a  potent  liver  extract  would  be  more  easily  ad- 
ministered, and  a  number  of  crude  extracts  were  developed  and  later 
used  widely  for  treating  patients  with  pernicious  anemia.  Many  liver 
extracts  were  manufactured  and  tested,  and  it  soon  became  obvious  that 
the  positive  hemopoietic  effect  varied  according  to  the  source  of  the 
material,  the  method  of  extraction  and  other  unknown  factors.  An  inten- 
sive search  in  many  laboratories  and  clinics  in  various  parts  of  the  world 
was  initiated  to  determine  the  exact  nature  of  the  potent  substance  or 
substances.   Strandell  and  his  associates  in  Scandinavia,  Karrer  and  his 

COPYRIGHT   1949  BY  THE  OXFORD  UNlVERSirV   PRESS,  INC. 

452 ('53) 


452(154)        VITAMINS  AND  VITAMIN  DEFICIENCIES 

co-workers  in  Switzerland  and  Dakin,  Ungley  and  West  working  in 
the  United  States  and  in  Great  Britain,  all  produced  high  concentrations 
of  this  material. 

About  three  years  ago  it  was  shown  that  both  folic  acid  and  thymine 
are  effective  in  producing  blood  regeneration  in  patients  with  certain 
macrocytic  anemias  in  relapse''',  and  it  also  was  shown  that  thev  neither 
prevent  nor  control  the  symptoms  arising  from  the  degeneration  of  the 
posterior  and  lateral  columns  of  the  spinal  cord"'".  Since  neither  of  these 
substances  was  found  in  great  concentration  in  most  of  the  liver  extracts, 
the  search  for  the  active  principle  in  liver  continued  unabated. 

All  attempts  to  isolate  the  crystalline  material  were  hindered  by  lack 
of  a  reliable  assay  method.  In  1947  Shorb'''  found  in  liver  extracts  a 
growth  factor  required  by  Lactobitcillus  lactis  Dorner  in  concentrations 
bearing  a  linear  relationship  to  the  potency  of  the  extracts  used  in  the 
treatment  of  pernicious  anemia.  Rickes,  Brink,  Koniuszy,  Wood  and 
Folkers"",  aided  by  this  assay  method,  isolated  small  amounts  of  a  red 
crystalline  compound  which  was  highly  active  for  the  growth  of  the 
Lactobacillus  lactis  Dorner  and  also  was  highly  active  in  initiating  a 
positive  hemopoietic  response  in  persons  with  pernicious  anemia.  Thc\' 
suoffirested  the  name,  vitamin  Bn-,  since  the  bioloi^ical  role  of  the  new 
compound  was  so  little  understood,  and  since  this  name  had  only  nutri- 
tional significance  and  connotation. 

Smith''''  in  Britain  isolated  the  same  type  of  cr^^stals  from  liver  eight 
days  after  the  Merck  publication.  He  and  his  associates  used  the  recently 
introduced  method  of  partition  chromatography  to  prepare  substances 
containing  approximately  3  per  cent,  of  the  active  principle.  Then  by 
treatment  with  trypsin,  followed  by  more  chromatography,  they  pro- 
duced tremendous  concentration  with  the  final  crystallization  from 
aqueous  acetone. 

Biochemistry  and  Physiology 

Vitamin  Bn-  is  a  red  crystalline  compound  which  has  not  been  pre- 
pared synthetically.  Microphotographs  of  this  vitamin  can  be  seen  in 
Fig.  67.  When  heated  on  the  micro-stage,  the  crystals  lose  their  red 
color  at  about  212°  C.  and  do  not  melt  below  300°  C. 

The  structural  fomiula  of  vitamin  Bi-  is  not  known.  Intensive  and 
excellent  studies  are  being  made  independently  by  Folkers  and  the 
Merck  Research  Laboratories  group-''  and  by  the  British  investigator, 
I',.  Lester  Smith''**  and  his  associates  in  the  Glaxo  Laboratories.  Emission 

\'^oi,.  1.  449 


BIOCHKAIISIRY  AND  PHYSIOLOGY 


45- ('55^ 


spectrographic  analysis  has  shown  the  presence  of  cobalt  in  the  vitamin 
Bii-  crystals.  The  vitamin  appears  to  be  the  first  cobalt  complex  detected 
in  human  or  animal  tissues.  It  appears  to  have  six  groups  arranged  about 
the  cobalt  atom,  and  the  bright  red  color  of  vitamin  B12  appears  to  be 
associated  with  this  cobalt  complex.  X-ray  crystallography  suggests 
that  the  molecular  weight  is  about  1,500  to  1,750.  The  results  of  the 
American  and  British  investigators,  although  arrived  at  independently 
and  often  by  different  techniques,  have  agreed  remarkably.   Both  croups 


Fig.  I.  Alicrophotograph  of  vitamin  B12  crystals.  (Courtesy  of  Dr.  Hans  Molitor, 
Alerck  Institute  of  Tiierapcutic  Research). 

not  only  have  found  the  cobalt  but  also  have  reported  the  presence  of 
phosphorus  and  nitrogen  in  the  compound.  The  nutritional  siijnificance 
of  cobalt,  piiosphorus  and  iron  for  animals  and  human  bcinos^will  have 
to  be  re-evaluated  when  the  biochemical  significance  of  vitamin  B12  is 
better  understood. 

\^itamin  Bij  is  rather  widely  distributed  in  relatively  high  amounts 
in  cow  manure,  fish  meal,  pancrcatin,  papain,  eggs,  whey,  milk  p()\\der, 
beef  extract  and  the  cultures  of  a  number  ot  microorganisms.    The 

Yoi..  I.  449 


452(«56)        VITAMINS  AND  VITAMIN  DEFICIENCIES 

natural  vitamin  then  may  be  said  to  occur  in  a  number  of  plant,  animal 
and  microbiological  materials,  yet  it  does  not  occur  in  abundance. 
Apparently  man  cannot  synthesize  the  material,  although  the  micro- 
organisms in  his  alimentary  tract  may  do  so,  nor  can  he  store  it  to  any 
great  degree  in  his  tissues. 


Pathological  Physiology 

Vitamin  Bij  or  substances  acting  similarly  are  required  in  minute 
amounts  to  maintain  most,  if  not  all,  forms  of  life.  It  is  necessary  for 
the  growth  of  certain  microorganisms.  It  stimulates  the  growth  of 
secondary-generation  rats  weaned  from  mothers  that  were  maintained 
during  gestation  and  lactation  on  a  diet  devoid  of  animal  protein.  It 
counteracts  the  growth-retarding  effect  of  thyroid  extract  when  fed 
to  immature  rats,  and  it  has  been  found  to  have  "animal-protein-factor" 
activity  in  chicks  obtained  from  hens  fed  all-vegetable-protein  rations. 
Thus,  there  is  a  possibility  that  vitamin  B12  is  identical  with,  or  closely 
related  to,  the  animal  protein  factor  recovered  from  cow  manure  and 
from  a  number  of  microorganisms^'^'  "^". 

When  patients  with  Addisonian  pernicious  anemia  in  relapse  are 
given  vitamin  B12,  it  produces  a  positive  hematologic  response"^*  and 
benefits  striking^ly  the  patient  who  has  acute  glossitis  and  acute  com- 
bined degeneration  of  the  spinal  cord.  It  has  been  found  to  be  effective 
in  producing  a  hemopoietic  response  and  great  symptomatic  improve- 
ment in  persons  with  nutritional  macrocytic  anemia,  tropical  sprue  and 
non-tropical  sprue"*"'  "*'■  -*^'  "*^'  "**'•  "*^  \\'hen  it  is  realized  that  this  material 
can  be  given  in  microgram  quantities  and  produce  regeneration  of  a  num- 
ber of  litres  of  blood  and  be  followed  bv^  a  great  increase  in  appetite  and 
body  weight,  it  must  be  thought  of  as  something  affecting  one  of  the 
profoundly  important  enzyme  systems  of  the  body. 


SyM  PTOM  ATOLOG  Y 

Vitamin  Bil>  has  been  isolated  so  recently  and  exists  in  the  pure 
state  in  such  minimal  quantities  that  vitamin  B12  deficiency  has  not  been 
described  as  such.  The  authors  are  of  the  opinion  that  pernicious  anemia 
can  be  considered  the  result  of  vitamin  Bi-  deficiency.  Pernicious 
anemia  is  too  well  known  to  repeat  a  description  of  it  here  in  detail. 

Voj..  I.  449 


PREVENTION  AND  TREATMENT  452(157) 

The  onset  is  characteristically  insidious.  The  initial  complaints  are 
fati<Tability,  weakness,  numbness,  tingling,  stiffness,  iieadache,  nausea, 
lack  of  appetite,  vomiting,  diz/.incss,  shortness  of  breath,  palpitation, 
diarrhea,  pallor,  abdominal  pain  and  glossitis.  By  the  time  the  anemia 
is  severe,  the  skin  and  sclerae  often  are  lemon  yellow  in  color.  By  this 
time  complaints  referable  to  the  nervous  system  are  present.  These  com- 
plaints may  be  associated  with  mental  disturbances,  peripheral  neuritis 
or  spinal  cord  degeneration.  iMacrocytosis  is  characteristic  of  the  blood 
in  persons  with  pernicious  anemia,  and  during  the  relapse  stage  the  bone 
marrow  is  hyperplastic.  Failure  to  secrete  free  hydrochloric  acid  in 
crastric  juice  after  histamine  stimulation  is  most  characteristic  of  persons 
with  this  disease. 


DlAC.NOSIS 

A  clinician  can  easily  diagnose  the  average  case  of  pernicious  anemia 
in  relapse.  Glossitis,  numbness  and  tingling  of  the  extremities,  weakness, 
macrocytic  anemia,  hyperplastic  bone  marrow  with  megaloblastic  arrest 
and  achlorhydria  form  a  clinical  picture  which  is  extremely  well  known. 
Atypical  cases  even  in  relapse  are  difficult  to  diagnose,  and  experts  may 
disagree  in  their  interpretations  of  the  findings.  The  most  competent 
physician  cannot  make  a  positive  diagnosis  when  the  patient  is  in  full 
remission,  irrespective  of  how^  thoroughly  the  physical  examination  and 
laboratory  studies  arc  made. 


Prexf.ntion  and  Treatment 

At  the  present  time  there  is  no  known  method  of  preventing  per- 
nicious anemia.  Since  it  cannot  be  prevented,  replacement  therapy  is 
essential.  The  hemopoietic  response  of  patients  in  relapse  with  perni- 
cious anemia,  nutritional  macrocytic  anemia  and  tropical  sprue  to 
vitamin  Bn-  is  shown  in  Figs.  2,  3  and  4,  respectively. 

\^itamin  Bn-  is  effective  in  promoting  regeneration  of  the  red  blood 
cells,  hemoglobin,  white  blood  cells  and  platelets  in  properly  selected 
patients,  but  we  do  not  have  sufficient  studies  to  recommend  the  aver- 
age dose  required  either  for  full  regeneration  or  for  maintenance.  As 
little  as  I  microgram  will  produce  a  detectable  blood  response  in  an 
occasional  case,  whereas  as  much  as  5  micrograms  may  fail  to  produce 

Vol.  I.  449 


^52(.58)        VITAMINS  AND  VITAMIN  DEFICIENCIES 

a  response  in  a  case  that  will  respond  well  follo^^'ing  the  administration 
of  lo  micrograms.  The  individual  variation  in  the  amount  required  can 
be  overcomt  however,  by  giving  increased  dosage.  \\c  have  seen  no 
case  that  did  not  respond 'somewhat  to  25  microgram  amounts,  and  we 
have  seen  no  case  that  did  not  regenerate  several  million  red  blood  cells 
when  as  much  as  100  micrograms  was  injected. 

H£/^OPO/£T/C    /i£SPOA/S£    Of   A    PAT/E/SfT    (D.H) 
l/^/TH     P£/lAy/C/OU3    ANEM/A      TO     V/TAM/M    B  ,z 


■2.  S 
o>  0 

12. 

11  . 

4. 

10. 

9. 

6. 

3. 

7- 

6. 

2. 

5. 

4. 

3. 

1  . 

2. 

0. 

0. 

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V/TA/^/N   &,2, 

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9     10    11      12     13    14    15    16    17     18    19    20 
DAY3 

Fig.  2. 


We  have  not  had  sufficient  material  to  study  properly  oral  therapy 
and  cannot  make  any  comment  about  it  at  this  time.  The  clinical  pos- 
sibilities of  vitamin  B,,  then  are  not  altogether  prcdicable,  although  it 

Vol.  I.  449 


pri:\t:mion  and  iri:aiail:nt 


45 :(  15V 


offers  the  physician  a  known  dose  of  a  pure  conipound  and  should  thus 
minimize  the  variation  in  therapeutic  response. 

Potent  doses  of  the  new  vitamin  may  be  given  without  physical  dis- 
comfort to  the  patient.  A  number  of  persons  with  pernicious  anemia 
develop  alleriry  to  liver  extracts,  and  in  some  parts  of  the  world  the 

H£MOPO/ET/C     R£SPO/V3f    OP    A      PAT/EA/T    (T.L.) 
h//r^    NUTfi/T/OAJAL    /^ACfiOCYT/C    AA^EM/A    TO    V/TAM/N    &,z 


11 


1. 


40 


30. 


to 
9. 
8. 

7 

6 

SA    20 

4. 


OJ       OJ 


VITAM/N    3,2, 

25  m/'crogroms    I.  M. 


^ 


10. 


9       10     11      12      1)      14     Id     1«      17      1ft     19     20 

DAYS 


Fig.  3. 

commercial  liver  extract  preparations  are  not  potent.  Persons,  who  have 
acute  manifestations  of  subacute  combined  degeneration  of  the  spmal 
cord,  are  benefited  when  given  vitamin  Bi-. 

Suffice  it  to  say  that  the  limitations  and  therapeutic  indications  of 
vitamin  B12  are  not  yet  fully  known,  but  it  is  by  far  the  most  potent 

Vol..  1.  449 


45:i(i6o)        VITAMINS  AND  VITAMIN  DEFICIENCIES 

therapeutic  agent  per  unit  of  weight  yet  introduced  into  medicine.  Un- 
fortunately it  is  still  in  the  experimental  stage,  and  the  supplies  of  vitamin 
Bi2  are  inadequate  as  yet  for  routine  treatment  of  pernicious  anemia. 

i^/TH    TROP/CAL     JP/^U£     TO       \^/ TA  A^ //\/  & ,, 


4. 

io. 

9. 

6. 

3. 

7. 

6. 

2. 

S. 

4. 

3. 

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1 

0 

40. 

v/rAM/r^  e>,t_ 

Z5   micrograms    I  Af. 

30, 

T 

/n^ 

QO. 

Hob                   /             V/ 

P.  AC          1      ,..-'•'''        *\ 

IO  . 

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Rei-ics.  1                                       \ 

O. 

r-^                                                           —7-^ 

1        Z       3       4       6       6       7       e       9      10     11      1Z     U     14      IS      16      17      IS      19      20 
DAYS 

VlG.  4. 


Toxicity 


The  practicing  physician  should  keep  in  mind  there  is  such  a  great 
difference  between  the  therapeutic  dose  and  any  theoretical  toxicity  of 
vitamin  Bn-  that  there  is  no  danger  of  even  accumulative  toxicity,  and 
he  should  remember  that  it  is  a  safe  and  effective  therapeutic  agent 
when  it  becomes  available  in  sufficient  amounts  to  use  in  practice. 

Vol.  I.  449 


BIBLIOGRAPHY  452(161) 

BIBLIOGRAPHY 

VITAMIN  Br2 

lyi.    MINOr,   G.   R.   and   MURPHY,   W.   P.:     Treatment   of   pernicious 
anemia  1)\-  a  special  diet.  Jour.  Am.  Aled.  Assoc,   1926,  LXXXVII, 

470. 

272.  SPIES,  T.  D.:    Experiences  \\  ith  folic  acid.  The  Year  Book  Publishers, 

Chicago,   1947. 

273.  SPIES,  T.  I),  and  STONE,  R.  E.:    Some  recent  experiences  with  vita- 

mins and  vitamin  deficiencies,  South.  Aled.  Jour.,   1947,  XL,  46. 

274.  SHORR,  Al.  S.:     Activity  of  vitamin  B^  for  the  growth  of  Lacto- 

bacillus lactis.  Science,  194H,  CAII,  397. 

275.  RICKES,  E.  L.,  BRINK,  N.  G.,  KONIUSZY,  F.  R.,  WOOD,  T.  R. 

and  FOLKERS,  K.:  Ovstalline  vitamin  B^^,  Science,  194S,  C^VII, 
396. 

276.  SAIITH,  E.  L.:    Purification  of  anti-pernicious  anaemia  factors  from 

liver.  Nature,  1948,  CLXI,  6^8. 

277.  RICKES,  E.  L.,  BRINK,  N.  G.,  KONIUSZY,  F.  R.,  WOOD,  T.  R. 

and  FOLKERS,  K.:  Y^itamin  Bi-.,  a  cobalt  complex.  Science,  1948, 
CVIII,  134. 

278.  SMITH,   E.   L.:     Presence  of   cobalt  in   the   anti-pernicious   anaemia 

factor.  Nature,   1948,  CLXII,   144. 

279.  OTT,   W.   H.,   RICKES,   E.   L.   and   WOOD,   T.   R.:     Activity   of 

crystalline  vitamin  Bi^  for  chick  growth,  jour.  Biol,  ('hem.,  1948, 
CLXXIV,  1047. 

280.  STOKSTAD,  E.  L.  R.,  PAGE,  A.,   IR.,  PIERCE,   J.,  FRANKLIN, 

A.  L.,  JUKES,  T.  H.,  HEINLE,  R.  W.,  EPSTEIN,  Al.  and 
WELCH,  A.  D.:  ActivitN'  of  microbial  animal  protein  factor  con- 
centrates in  pernicious  anemia.  Jour.  Lab.  and  (^lin.  Med.,  1948, 
XXXIII,  860. 

281.  WEST,  R.:  Activity^  of  vitamin  Bio  in  Addisonian  pernicious  anemia. 

Science,  1948,  (]\1I,  398. 

282.  SPIES,  T.  D.,  STONE,  R.  E.  and  ARAMBURU,  T.:    Observations 

on  the  antianemic  properties  of  vitamin  B,^,  South.  Aled.  Jour., 
1948,  XLI,  522. 

283.  SPIES,  T.  D.,  GARCIA  LOPEZ,  G.,  AllLANES,  F.,  LOPEZ  TOCA, 

R.  and  CULATR,  B.:    Observations  on  the  hemopoietic  response  of 
persons  with  tropical  sprue  to  vitamin  Bi-.,  South.  Aled.  Jour.,  1948, 
XLI,  523. 
Vol.  I.  449 


452(162)        X'lTAMlNS  AND  XIIAAIIN  DEFICIENCIES 

284.  SPIES,  T.  D..  STONE,  R.  E.,  GARCIA  EOPEZ,  G.,  MIEANES,  F., 

ARAMBURU,  T.  and  LOPEZ  TOCA,  R.:  The  association  be- 
tween gastric  achlorh\dria  and  subacute  combined  degeneration  of 
the  spinal  cord.  Postgraduate  Medicine,    194H,  \\\  89. 

285.  BERK,  L.,  DENNY-BROWN,  D.,  FINLAND.   M.  and  CASTLE, 

W.  B.:  Effectiveness  of  vitamin  B,-  in  combined  s\  stem  disease, 
New  Eng.  Jour.  Med.,  1948,  CCXXXIX,  328. 

286.  SPIES,  T.  b.,  STONE,  R.  E.,  KARTUS,  S.  and  ARAiMBURU,  T.: 

The  treatment  of  subacute  combined  degeneration  of  the  spinal  cord 
with  vitamin  Bi-,  South.  Med.  Jour.,   1948,  XLI,   1030. 

287.  SPIES,  1".  D.  and  SUAREZ,  R.  M.:     Response  of  tropical  sprue  to 

vitamin  Bi^,  Blood,  1948,  111,  1213. 
June  I,  194Q 


\'()i..  1.  449 


CHAPTER  XI 

CLIMATE    IN    HEALTH    AND    DISEASE 
By  clarence    A.    MILLS 

Table  of  Contents 

.     ^. 453 

Introduction 

Physiological  Considerations  of  Climatic  Effects 455 

Human  Energetics '^^^ 

Growth  Rates  at  Different  Temperature  Levels 459 

Development  of  Sexual  Function 4^  i 

Resistance  to  Infections 4  3 

Vitamin  and  Protein  Requirements 4^5 

Climate  and  Disease 4/ 

Diabetes  Mellitus .      .      •  473 

Pernicious  Anemia,  Toxic  Goiter  and  Addison's  Disease       .      .      .  47» 

Arteriosclerosis  and  Heart  Failure 47'8 

^  482 

Cancer 

Leukemia 

Infectious  Diseases 4  4 

Acute  Appendicitis,  Acute  Nephritis 495 

Heat  Stroke,  Heat  Exhaustion  and  Heat  Cramps '^^^  ^  x 

Sickness  and  Health  Tides 500  (i 

Climatic  Therapy coo  (O 

Metabolic  Diseases -^      ^i^ 

Toxic  Goiter  and  Hyperthyroid  States 500  J4i 

Pernicious  Anemia 500  ^5^ 

Arteriosclerosis,  Hypertension  and  Heart  Failure ^"^6) 

Nervous  Disturbances ^^°  /  ! 

X   r      •         T^-  ....  500  (7) 

Infectious  Diseases )\ 

Tuberculosis 500   9) 

Rheumatic  Infections 500  (lOj 

500  (11) 

*      * 500  (12) 

500  (13) 


Leprosy 
Air  Conditioning 
Bibliography 


Introduction 
Climate  as  a  factor  in  the  health  of  man  is  now  beginning  to  receive 

COPYRIGHT   1941   BY   THE  OXFORD   UNIVERSITY  PRESS,  NEW  YORK,   INC. 

453 


454  CLIMATE   IN    HEALTH   AND    DISEASE 

the  attention  its  importance  warrants.  Through  its  dominance  of  ease  of 
body  heat  loss,  it  largely  determines  the  energy  level  upon  which  man 
may  exist  in  a  given  region,  and  we  now  know  that  much  more  than  mere 
working  ability  is  attached  to  this  energy  level  of  existence.  All  vital 
functions  of  the  body  are  based  upon  the  energy  derived  from  cellular 
combustion  of  foodstuffs,  but  as  an  energy  conversion  machine  the  body 
is  not  of  high  efficiency.  It  is  thus  very  sensitive  to  the  ease  with  which 
its  waste  heat  can  be  thrown  off,  and  it  is  here  that  climatic  dominance 
is  exercised.  Where  heat  loss  is  accomplished  easily,  growth  is  most 
rapid,  maturity  comes  early,  resistance  to  infection  is  highest,  energy  for 
thought  and  action  is  most  plentiful,  and  health  assumes  a  more  positive 
and  dynamic  quality.  As  heat  loss  becomes  more  difficult,  all  these  in- 
dices of  vitality  are  depressed,  and  a  lower,  more  vegetative  level  of 
existence  results. 

Particularly  in  America  with  its  intense  climatic  contrasts  should 
there  be  among  physicians  a  clear  understanding  of  these  forces  at  work. 
Enlightened  medical  practice  now  goes  far  beyond  the  mere  diagnosis  and 
treatment  of  disease.  Underlying  most  research  into  the  treatment  of 
disease  has  lain  the  ideal  of  disease  prevention,  the  maintenance  of  un- 
hindered health.  Among  the  factors  influencing  this  maintenance  of 
health  climatic  environment  probably  will  be  found  to  be  equally  as  im- 
portant as  adequate  food  supply  or  genetic  background.  Proper  food  is, 
of  course,  an  essential  requirement,  but  so  too  is  the  ability  to  utilize  this 
food.  With  the  lower  combustion  level  of  people  in  tropical  warmth 
more  vitamins  are  needed  to  utilize  each  gram  of  food  than  are  required 
for  optimal  response  in  cooler  climates.  Man  is  less  energetic  in  warm 
climates,  but  he  is  a  more  efficient  working  machine  and  shows  less  evi- 
dence of  wear  and  tear.  In  cooler  regions,  where  more  dynamic  and 
buoyant  health  prevails,  the  most  acute  and  worrisome  problems  facing 
the  medical  profession  arise  from  the  wear  and  tear  of  too  stressful  an 
existence. 

While  mean  temperature  level  and  ease  of  body  heat  loss  thus  dom- 
inates the  energetics  of  life,  there  is  a  second  climatic  factor  which  in 
some  regions  seriously  disturbs  the  smooth  flow  of  healthful  functioning. 
Storminess  or  atmospheric  turbulence  with  the  accompanying  sudden 
changes  in  temperature,  pressure,  humidity,  etc.,  is  now  recognized  as  a 
major  disturbing  factor  in  certain  regions  of  the  earth  where  cyclonic 
storms  prevail.  These  sudden  changes  in  the  atmosphere  seriously  disrupt 
tissue  functioning  in  ways  as  yet  little  understood  and  seem  closely  re- 
lated to  the  initiation  of  many  types  of  acute  infectious  attacks.  Storm 
changes  certainly  constitute  a  major  health  factor  in  regions  where  they 

Vol.  I.  941 


PHYSIOLOGICAL  CONSIDERATIONS  455 

are  frequent  and  abrupt,  but  much  more  evidence  must  be  accumulated 
before  the  physiology  of  their  effects  can  be  understood  clearly.  Physi- 
cians should  realize  that  individuals  differ  greatly  in  their  sensitiveness  to 
storm  changes.  Some  are  utterly  unfitted  for  existence  in  a  stormy  region 
and  should  be  advised  of  the  advantages  of  migration  to  a  region  of  less 
turbulence. 

This  chapter  is  offered  in  the  hope  that  it  may  help  physicians  to  a 
clearer  understanding  of  the  workings  of  these  climatic  factors.  Knowl- 
edge in  this  field  still  is  in  the  stage  of  rapid  expansion,  but  sufficient 
definite  information  already  is  at  hand  to  warrant  positive  advice  along 
several  lines.  Such  advice  will  be  presented  in  the  final  pages  of  the 
chapter,  after  the  mechanism  and  details  of  climatic  effects  have  been 
discussed.  The  newness  of  much  of  this  field  of  knowledge  necessitates, 
for  its  clear  understanding,  a  rather  comprehensive  presentation  of  the 
physiological  principles  involved. 

Physiological  Considerations  of  Climatic  Effects 
Human  Energetics 

Since  the  most  fundamental  effects  of  climate  are  exerted  upon  the 
energetics  of  human  existence,  let  us  first  consider  the  body  as  an  energy 
conversion  machine.  At  all  times  it  lives  and  functions  only  by  virtue 
of  the  cellular  combustion  of  foodstuffs.  Much  of  this  combustion  energy 
is  wasted,  however,  because  of  low  working  efficiency.  Man  himself  has 
designed  a  machine  of  greater  working  efficiency  than  is  the  human 
body.  As  high  as  37  per  cent,  efficiency  has  been  reached  in  Diesel  en- 
gines, while  even  gasoline  motors  may  reach  the  20  to  25  per  cent,  effici- 
ency exhibited  by  man  (i),  the  horse  (2)  and  the  dog  (3).  The  human 
body,  however,  is  much  more  limited  than  are  inanimate  motors  in  the 
temperature  range  within  which  it  can  function  well.  Even  a  very  few- 
degrees  of  rise  or  fall  from  the  normal  body  temperature  level  seriously 
interferes  with  efficient  functioning. 

To  meet  this  handicap,  the  body  has  developed  an  intricate  mechanism 
for  control  of  rate  of  heat  loss.  Through  the  vasomotor  control  of  blood 
supply  to  the  skin  the  amount  of  heat  reaching  the  body  surface  for  heat 
dissipation  can  be  altered  with  great  rapidity.  Normal  heat  loss  from  the 
deeper  tissues  by  direct  conduction  is  slow  and  is  impeded  by  the  insulat- 
ing layers  of  fat  encountered,  but  the  blood  with  its  high  specific  heat 
capacity  and  rapid  circulation  can  carry  internal  heat  to  the  body  surface 
at  a  rapid  rate.     Blood  flow  through  skin  capillaries  may  be  increased  as 

Vol.  I      941 


456 


CLIMATE   IN   HEALTH   AND   DISEASE 


much  as  30-fold  within  a  few  minutes  when  a  sudden  need  arises.  When 
this  increased  blood  flow  through  the  skin  proves  inadequate  for  quick 
elimination  of  the  heat  of  combustion,  then  the  sweat  glands  become  ac- 
tive and  make  possible  a  still  greater  increase  in  rate  of  heat  loss  by- 
water  vaporization. 

This  intricate  heat-control  mechanism  functions  quickly  to  meet  sud- 
den changes  in  heat  production,  as  in  bodily  activity,  or  in  the  ease  of 


not) 


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OCr|N0v}  Ofc}jANj  FCBlMAWjAfKlf^YlJUN  jjt>LYJAUcjs£p}oCT  \nOV 


Mean  monthly  metabolism  and  mean  monthly  temperature. 
Gessler  (1925),  observations  on  himself. 

Fig.  I.  Seasonal  variations  in  oxygen  consumption. 

heat  loss,  as  in  sudden  external  temperature  changes.  However,  with 
more  prolonged  changes  in  the  ease  or  difficulty  of  heat  loss,  the  body 
adapts  by  an  increase  or  decrease  in  its  basic  rate  of  tissue  combustion. 
Thus,  external  heat  that  lasts  only  a  few  days  calls  into  play  only  the 
vasomotor  and  sweating  mechanisms,  but  if  such  heat  persists  for  10  days 
to  2  weeks,  then  there  occurs  a  marked  suppression  in  tissue  combustion 
rate.  Therein  lies  the  chief  reason  why  severe  summer  heat  waves  may 
persist  for  weeks  but  cause  frequent  prostration  and  death  in  the  af- 
fected population  only  during  the  first  10  days  or  so. 

It  is  this  combustion  rate  response  to  the  more  prolonged  changes  in 
external  temperature  level  and  ease  of  body  heat  loss  that  holds  greatest 
significance  for  man.     Any  decrease  in  total  tissue  combustion  level,  en- 

VoL.  I.  941 


PHYSIOLOGICAL   CONSIDERATIONS 


457 


forced  by  difficulty  in  heat  loss,  necessarily  must  mean  a  curtailment  of 
energy  available  for  carrying  out  such  vital  functions  as  growth,  work 
performance,  tissue  repair  and  the  fight  against  infectious  invasions. 
Such  direct  linking  of  these  vital  functions  to  tissue  combustion  rate  and 
ease  of  body  heat  loss,  although  logical  enough,  has  not  received  the 
appreciation  its  importance  warrants.  Indeed  there  has  existed  among 
medical  men  in  America  a  disbelief  that  any  such  dependence  really  exists. 
This  disbelief  dates  back  to  the  publication  of  a  paper  by  Benedict  and 


JUNE  so     JULY  5  JO  IS  20  25  ZO 

Daily  observation  of  basal  metabolism  of  C.  J.  M.  during  a  voyage 
from  London  to  Australia,  June-July,  1923,  and  daily  record  of  the 
temperatures  of  the  dry  and  wet  bulb  thermometers  at  7  A.M. 

Fig.  2.  Fall  in  oxygen  consumption  in  tropical  heat. 


CathcartS  in  which  they  cite  oxygen  consumption  data  on  14  subjects  in 
Boston  and  claim  a  lack  of  any  seasonal  influence.  Even  though  their 
own  data  presented  in  their  article  do  show  a  strong  tendency  for  lowest 
consumption  rate  to  occur  in  July  or  August,  and  this  in  Boston  where 
summer  heat  is  rarely  severe,  this  article  has  been  extensively  quoted 
Vol.  I.  941 


458 


CLIMATE   IN   HEALTH   AND   DISEASE 


since  as  indicating  that  tissue  combustion   rates  are  independent  of  ex- 
ternal temperature  levels. 

This  point  is  of  such  basic  importance  in  any  analysis  of  climatic 
effects  that  recently  it  was  made  the  subject  of  a  special  article\  in  which 
the  available  evidence  was  presented  and  discussed.  As  set  forth  in  that 
article  the  evidence  points  conclusively  to  a  clear  inverse  relationship 
between  tissue  combustion  rates  and  prevailing  external  temperature  levels 
in  both  men  and  animals.  Fig.  i  shows  this  relationship  as  found  by 
Gessler^  through  all  seasons  of  a  year  at  Heidelberg,  Germany.  Fig.  2 
indicates  the  marked  suppression  in  resting  oxygen  consumption  rate 
I     I     I     I     I     I     I     I 


I     I 


.<:?'^- 


• • —  CONTROL  GROUP  (70-75°P) 

X — 3C —  COLD  ROOM  GROUP  (65°?) 
HOT  ROOM  GROUP  (90°?) 


II  I 


11 


I  t 


13 


15 


17 


19 


21 


AGE   IN  WEEKS. 
Fig.  3.  Growth  of  white  mice  at  different  temperatures, 
found  by  Martin^  in  himself  during  his  passage  through  the  zone  of  tropi- 
cal heat  on  a  trip  from  London  to  Melbourne.     Practically  all  investiga- 
tors, who  have  looked  for  this  heat  suppression  of  combustion  rate,  have 
found  it.     Let  us  next  see  what  it  means  in  terms  of  growth  and  other 
vital  functions. 
Vol.  I.  941 


PHYSIOLOGICAL  CONSIDERATIONS  459 

Growth  Rates  at  Different  Temperature  Levels 

All  types  of  experimental  animals  suffer  a  growth  retardation  when 
heat  loss   becomes   difficult.      Fig.    3   shows   the   extent   of   th,s  growth 
suppr  s son   n  white  mice  kept  at  65°  F.,  7^°  F.  and  9.°  F.    Th.s  happens 
Tven    hough  all  factors  of  existence  other  than  ease  of  heat  loss  are  kep 
instant.     Animals  at  9.°  F.  eat  only  about  half  as  much   food  as  at 

FOOD    CONSUMPTION  &  RAT  GROWTH   RATES 
AT  DIFFERENT  TE/V\PER.ATUR.E    LEVELS 


300 


, .  Food   consumed /rat /week. 

• •   Body   weight 


50 


12    MOM     THIAMINt/KILO    OF    RATION 


4  5 

WEEKS 


Fig.  4. 


Food  consumption  and  growth  rates  in  heat  and  cold. 


6=;°  F  In  Fig.  4  is  shown  this  difference  in  food  consumption  by  young 
Wistar  rats  and  its  direct  relationship  to  their  rate  of  growth  and  final 
Tdult  size.  Herein  lies  the  principal  reason  why  domestic  -^^f  .t^r 
poorly  in  tropical  warmth,  giving  lean,  strmgy  meat  of  ^^-ong  flavor 
Coarseness  of  the  tropical  forage  crops  and  leaching  of  soils  under  the 
heavy  rainfall  may  be  factors  of  considerable  weight,  but  suppression  of 
Vol.  I.  941 


46o  CLIMATE   IN   HEALTH   AND   DISEASE 

tissue  combustion  rate  by  difficulty  in  body  heat  loss  probably  is  more 
important. 

Children  show  this  same  retarded  growth  rate  and  inferior  adult  size 
under  tropical  heat  conditions,  while  in  the  optimal  coolness  of  middle 
temperate  regions  growth  is  most  lusty  and  adult  stature  greatest^.  The 
close  relation  of  such  growth  differences  to  oxygen  utilization  is  empha- 
sized by  the  marked  differences  in  vital  lung  capacity  exhibited  by  in- 
dividuals from  the  two  types  of  climate.  Vital  capacity  in  Filipino  college 
students  is  only  a  little  over  half  as  great  as  that  of  students  in  northern 
United  States. 

Back  through  human  history  man's  stature  and  development  has 
fluctuated  with  slow  changes  in  earth  temperatures.  Middle  Age  warmth 
saw  a  marked  decline  from  early  Greek  levels  in  the  size  of  man  and  in 
his  speed  of  development,  while  with  the  colder  centuries  since  the  time 
of  the  Renaissance  the  race  has  again  shown  a  striking  rise  from  the  low 
Middle  Age  standards.  The  menarche  in  girls  of  early  Greece  came  at 
13  years  of  age  according  to  Hippocrates,  but  with  the  retarded  develop- 
ment of  the  Middle  Ages  the  menses  did  not  begin  until  the  i6th,  17th 
and  1 8th  years  in  European  girls.  A  marked  quickening  in  development 
has  been  in  evidence  during  the  last  few  centuries  of  lower  world  tem- 
peratures with  the  menses  now  coming  i^  years  earlier  than  they  did 
even  4  decades  ago  and  the  adult  male  height  being  now  four  inches 
greater  than  in  Revolutionary  days.  Man  was  really  runt-like  through 
the  warm  centuries  of  the  Middle  Ages,  small  of  stature  and  fine-boned. 
The  knights,  who  wore  the  suits  of  armor  now  on  display  in  museums, 
although  probably  the  best  physical  specimens  of  the  day,  must  have 
been  far  below  the  standards  of  today,  for  a  well-developed  American  boy 
of  14  years  would  have  great  difficulty  getting  into  any  of  the  suits  now 
on  display  in  the  Tower  of  London. 

World  temperatures  have  been  rising  quite  generally  again  in  recent 
decades,  and  the  long  period  of  improvement  in  racial  physique  seems 
perhaps  about  at  an  end.  College  youth  in  America,  where  nutritional 
standards  have  never  been  higher,  are  now  showing  signs  of  a  reversal 
in  the  growth  tide.  The  menses  are  now  tending  to  begin  later  and  the 
stature  to  be  slightly  less  with  each  year's  entering  class  of  freshmen  in 
schools  of  lower  and  middle  temperate  latitudes,  although  improvement 
still  proceeds  apace  in  schools  of  higher  latitudes  where  depressive  summer 
heat  has  not  yet  reached  effective  levels.  The  human  race  does  then 
seem  to  respond  to  slow  changes  in  earth  temperature  levels  in  the  same 
manner  that  experimental  animals  respond  to  artificial  changes  in  ease  of 
body  heat  loss.     This  fact  is  of  fundamental  importance  in  racial  welfare. 

Vol.  I.  941 


PHYSIOLOGICAL   CONSIDERATIONS  461 

for  it  perhaps  accounts  in  large  part  for  the  slow  undulations  of  advance 
and  recession  which  the  race  has  undergone  through  past  ages  and  may 
some  day  give  a  clue  to  our  course  through  the  coming  decades  and  cen- 
turies, when  we  shall  have  become  able  to  predict  future  temperature 
trends.  The  matter  is  not  just  one  of  recession  in  rate  of  growth  and 
development  but  involves  also  all  the  other  factors  of  life  dependent  upon 
the  dynamics  of  cellular  combustion.  Ability  and  urge  to  accomplish 
along  both  physical  and  mental  lines  and  the  positiveness  of  health  itself 
seem  closely  bound  up  in  this  temperature  dominance  over  human  dy- 
namics. 

Development  of  Sexual  Functions 

Onset  of  sexual  functions  and  degree  of  fertility  are  closely  linked  to 
ease  of  body  heat  loss  and  tissue  combustion  level.  Most  rapid  develop- 
ment and  highest  fertility  occur  at  environmental  temperatures  around 
65°  F.  As  difficulty  in  heat  loss  comes  on  and  growth  rate  slackens,  we 
regularly  see  also  a  later  onset  of  sexual  cycles  in  young  females,  both 
human  and  animal,  and  a  lowered  fertility^.  Animals  mate  freely  at 
90°  F.,  but  conceptions  are  difficult  to  obtain  and  result  in  small  litters 
of  puny  young,  while  at  65°  F.  almost  every  mating  results  in  a  large 
litter  of  lusty  offspring.  Histological  changes  in  gonadal  tissues  indicate 
that  this  suppression  of  reproductive  tissue  is  extensive  and  very  real. 
Spermatogenic  activity  in  the  testes  is  almost  obliterated  within  10  to  14 
days  of  application  of  tropical  moist  heat.  After  several  weeks  of  adapta- 
tion some  recovery  of  function  occurs  but  to  a  much  lower  level  of  ac- 
tivity than  is  seen  at  lower  temperature  levels. 

Man,  living  under  natural  climatic  habitats,  shows  just  as  striking 
sexual  variations  at  different  levels  of  environmental  temperature  as  do 
laboratory  animals.  Onset  of  the  menses  in  girls  occurs  earliest  in  middle 
temperate  latitudes  and  comes  at  a  progressively  later  age  as  more  and 
more  severe  tropical  heat  is  encountered.  At  the  present  time  here  in 
North  America  earliest  menarche  is  found  in  the  upper  half  of  the  Mis- 
sissippi basin.  Nowhere  else  on  earth  do  children  grow  with  such  lusty 
vigor  and  enter  such  early  adolescence.  Development  in  the  Gulf  States 
is  somewhat  retarded  by  the  long  summer  of  tropical  moist  heat,  but 
most  severe  suppression  takes  place  in  the  tropical  lowlands,  where  de- 
pressive moist  heat  renders  heat  loss  difficult  at  all  times. 

Medical  literature  and  lay  belief  back  through  the  centuries  at  least 
to  the  time  of  Hippocrates  has  held  that  earliest  onset  of  the  menses 
occurred  in  the  tropics.     Even  though  all  recorded  statistics  contradicted 

Vol.  I.  941 


462 


CLIMATE   IN    HEALTH   AND    DISEASE 


this  belief,  still  it  is  encountered  among  people  of  all  lands,  both  lay  and 
medical.  Since  we  know  it  has  been  handed  down  through  medical  litera- 
ture for  two  thousand  years  without  factual  support,  we  can  well  presume 
that  it  may  have  originated  several  thousand  years  earlier  still.  Only 
20,000  or  so  years  ago  present  middle  temperate  regions  had  polar  cli- 
mates, and  optimal  temperature  conditions  for  man  were  to  be  found  only 
in  what  are  now  tropical  or  subtropical  lands.  That  such  beliefs,  perhaps 
once  based  upon  real  facts,  can  be  handed  down  through  many  thousands 
of  years  without  further  supporting  factual  background  is  well  illustrated 
by  the  ancient  astrological  beliefs  so  widely  held  today  even  among  in- 
telligent people. 


1926-8  Mean  of 
conceptions  by 
month. 


1924-8  Mean  Temp. 


Jan     Feb  Mar     Apr  May  J\ine   July  Aug  Sept  Oct  Nov  Dec 
Charleston,   S.C. 

Fig.  5.  Variations  in  conceptions,  Charleston,  S.  C. 

Fig.  5  illustrates  the  sharp  suppression  of  human  fertility  that  comes 
with  difficulty  in  heat  loss.  Wherever  human  populations  are  exposed  to 
seasonal  swings  in  mean  monthly  temperature,  highest  conception  rates 
nearly  always  occur  when  the  mean  temperature  level  is  near  65°  F.  As 
mean  temperatures  rise  above  70°  F.  or  fall  below  40°  F.,  fertility  is  re- 
duced. With  really  severe  moist  warmth,  as  in  Japan's  monsoon  summer 
heat  or  in  the  prolonged  severe  heat  waves  of  the  upper  Mississippi  valley 

Vol.  I.  941 


PHYSIOLOGICAL   CONSIDERATIONS  463 

in  North  America,  conceptions  may  be  reduced  as  much  as  50  per  cent. 
Nor  is  this  reduction  in  conceptions  merely  a  result  of  less  frequent  inter- 
course in  hot  weather,  for  there  occurs  no  significant  reduction  in  the 
frequenting  of  houses  of  prostitution.  Apparently  both  men  and  animals 
continue  the  mating  urge  in  hot  weather  but  suffer  a  sharp  drop  in  bio- 
logical fertility. 

There  has  been  much  written  about  child-mothers  among  tropical 
peoples,  but  it  is  really  among  populations  of  middle  temperate  regions 
that  fertility  has  its  earliest  onset.  Later  marriage  ages  of  the  more 
highly  industrialized  nations  of  the  temperate  zones  tend  to  mask  the 
early  onset  of  fertility,  but  it  has  been  brought  out  by  a  study  of  illegiti- 
mate first-births^°.  At  Cincinnati,  Ohio,  the  average  maternal  age  at 
illegitimate  first-birth  was  found  to  be  18.1  years  and  at  Richmond, 
Virginia,  18.2  years  for  negro  girls,  while  at  Panama  it  was  19.3  years  and 
in  the  Philippines  21.8  years.  The  average  lag  from  menarche  to  first 
conception  with  these  illegitimate  first-births  was  3.9  years  at  Cincinnati, 
4.0  at  Richmond,  4.5  at  Panama  and  6.3  in  Manila.  This  markedly  later 
age  at  first  conception  in  the  tropics  occurs  even  in  the  face  of  a  much 
greater  promiscuity  of  premarital  intercourse  and  lessened  likelihood  of 
chances  for  eflfective  impregnation  being  missed.  Maternal  age  at  the 
first  child-birth  in  Manila  is  the  same  regardless  as  to  whether  the  mother 
be  married  or  single. 

Malnutrition  from  any  cause  tends  to  retard  development  of  the  sexual 
functions.  Difficulty  in  body  heat  loss  is  no  more  effective  in  this  respect 
than  is  inadequacy  of  available  food  supply,  either  in  total  amount  or  in 
composition,  or  serious  childhood  illnesses.  The  menarche  usually  is  de- 
layed in  girls  who  have  been  subjected  to  any  of  these  depressing  influ- 
ences through  their  childhood  years. 

Resistance  to  Infection 

Although  such  factors  as  malnutrition,  vitamin  deficiency  and  exhaus- 
tion usually  have  been  considered  important  in  determining  the  body's 
ability  to  fight  infection,  there  has  been  little  apparent  inclination  to 
relate  this  ability  to  tissue  combustion  level.  Yet  such  a  relationship 
would  seem  logical,  since  all  vitality  factors  must  have  their  functional 
basis  in  the  energy  liberated  from  such  combustion.  It  is  infectious 
disease  which  kills  people  living  under  depressing  tropical  warmth,  while 
the  more  energetic  residents  of  middle  temperate  regions  die  mainly  from 
the  degenerative  and  breakdown  ailments.  In  1932  we  showed  that 
ability  to  survive  tuberculous  infection  was  markedly  higher  in  Cincinnati 

Vol.  I.  941 


464  CLIMATE   IN   HEALTH   AND    DISEASE 

residents  who  were  born  in  the  North  than  in  those  born  in  the  Gulf 
States".  Deahng  only  with  tuberculosis  deaths  among  the  indigent 
population  of  Cincinnati  it  was  shown  that  the  survival  time  from  first 
symptom  to  death  was  almost  twice  as  long  in  patients  born  in  northern 
United  States  or  North  Central  Europe  than  it  was  in  those  born  in  the 
Gulf  States  of  North  America  or  in  the  Mediterranean  countries  of 
Europe.  Ability  to  survive  acute  appendicitis  attacks  also  is  markedly 
higher 'in  the  North  than  in  the  South^^.  These  facts  will  be  discussed 
more  fully  on  a  subsequent  page. 

RESISTANCE    TO  INFECTION   IN  MICE  (PNEUMOCOCCUS) 


lO  ZO  30  40  50  60  70  flO  90  lOO 

HOURS      AFTER.    INOCULATION 

Fig.  6.  Resistance  to  infection  in  heat  and  cold. 

Human  disease  statistics,  however,  are  influenced  by  too  many  ex- 
traneous factors  to  be  of  any  great  value  in  determining  climatic  eflfects, 
unless  they  can  be  substantiated  by  studies  on  experimental  animals 
under  carefully  controlled  conditions.  Human  data  may  supply  indica- 
tions of  existing  differences  or  trends,  but  conclusive  proof  in  such  a  mat- 
ter must  come  from  laboratory  studies.  Fortunately  such  studies  have 
now  shown  that  ability  to  fight  infection  is  definitely  higher  under  con- 
ditions that  facilitate  body  heat  loss  than  it  is  where  heat  loss  is  difficult. 
With  all  other  existence  factors  except  ease  of  body  heat  loss  held  con- 
stant, practically  all  mice  adapted  to  90°  F.  will  be  dead  after  inoculation 
with  a  given  dose  of  pneumococci  organisms  before  those  adapted  to 
65°  F.  even  begin  to  succumb.  Fig.  6  presents  this  fact  in  striking 
fashion,  and  if  one  uses  a  less  lethal  organism,  such  as  a  hemolytic  strepto- 

VoL,  I.  941 


PHYSIOLOGICAL  CONSIDERATIONS  465 

coccus,  then  the  minimum  lethal  dose  for  the  65°  F.  mice  is  found  to  be 
about  four  times  as  great  as  it  is  for  those  kept  at  90°  F.  Antibody  pro- 
duction after  typhoid  vaccine  injection  into  rabbits  is  almost  twice  as 
great  in  those  animals  kept  at  the  lower  temperature. 

Locke^^  has  provided  support  also  for  the  idea  that  combustion  level  is 
an  important  factor  in  determining  resistance  to  infection.  He  found 
that  ability  of  animals  to  survive  pneumococcic  inoculations  or  of  human 
beings  to  maintain  freedom  from  respiratory  infection  was  related  directly 
to  their  rate  of  oxygen  utilization.  The  matter  needs  more  thorough 
study,  but  in  the  main  it  would  seem  that  man's  susceptibility  to  infec- 
tion and  his  chances  for  survival  are  conditioned  rather  markedly  by  his 
ease  of  body  heat  loss  and  the  resulting  tissue  combustion  level  allowed 
him.  Temperate  zone  man  does  not,  then,  enjoy  greatest  freedom  from 
respiratory  disease  during  the  summer  months  because  of  better  tissue 
vitality  as  has  been  so  commonly  supposed.  Actually  the  fatality  rate 
per  100  cases  of  acute  appendicitis  is  almost  twice  as  high  in  summer 
heat  as  in  northern  winter  cold,  and  tuberculosis  runs  its  most  rapid 
course  when  symptoms  of  disease  activity  first  appear  in  summer  heat. 
It  would  now  seem  almost  certain  that  the  summer  freedom  from  res- 
piratory infection  is  attributable  in  very  large  part  to  the  lessened 
storminess  of  that  season  and  the  greater  freedom  from  body  chilling. 
More  will  be  said  about  this  subject  on  a  later  page. 

Vitamin  and  Protein  Requirements 

Since  human  vitality  and  energy  level  seem  so  dependent  upon  ease 
of  body  heat  loss  and  tissue  combustion  rate,  it  is  well  to  look  into  the 
combustion  process  itself.  Perhaps  tissue  requirements  for  the  combustion 
catalysts  are  higher  when  the  combustion  rate  is  slowed  down  by  difficulty 
in  heat  loss.  With  the  lowered  food  intake  of  hot  climates  or  in  summer 
heat  it  may  well  be  that  a  higher  dietary  content  of  thiamine  and  of 
other  combustion  catalysts  of  the  vitamin  B  group  is  needed  to  maintain 
optimal  concentration  for  proper  tissue  oxidative  processes.  It  has  quite 
generally  been  considered,  largely  as  a  result  of  Cowgill's  studies**,  that 
thiamine  requirement  is  determined  by  the  amount  of  glucose  there  is  to 
be  burned,  that  a  more  or  less  constant  ratio  exists  between  thiamine  re- 
quirement and  total  non-fat  calories  of  the  diet.  His  studies,  however, 
and  those  of  others  in  this  field  were  carried  out  at  approximately  optimal 
environmental  temperatures  for  the  animal  subjects,  so  that  there  was  no 
way  of  knowing  whether  this  ratio  might  not  vary  as  external  tempera- 
tures were  raised  or  lowered. 

Vol.  I,  941 


466 


CLIMATE   IN   HEALTH   AND    DISEASE 


In  more  recent  studies  on  this  point'^  it  has,  in  fact,  been  found  that 
the  optimal  requirement  for  dietary  thiamine  is  twice  as  high  at  91°  F. 
than  it  is  at  65°  F.  Animals  show  definite  inadequacy  in  the  heat  at 
dietary  thiamine  levels  twice  as  high  as  those  at  which  inadequacy  ap- 

DIETARY  THIAMINE  AND  FOOD  CONSUMPTION  IN 
HEAT  AND  COLD 


150- 
140' 
130- 
HO- 
MO- 
100- 

90- 
SO- 
TO- 
60- 

50- 
40- 
30' 

20 
lO 
O' 


90-91"  F 
60%  RH 


3      10     n    24     31     38    45 
DAYS 


— T 1 1 1 1 1 

3      10     n     24     31     38    45 
DAYS 


MGS.  THIAMINE   PER  KILO  OF  FOOD 

1  =  0.2       4  «  0.8 

2  =   0.4       S  --   1.2 

3  =  0.6       6  '   1.6 

Fig.  7.  Dietary  thiamine  and  food  consumption  in  heat  and  cold. 

pears  in  a  cool  environment.     Studies  in  progress  indicate  that  somewhat 
similar  findings  will  be  obtained  for  others  of  the  vitamin   B  fractions, 
pantothenic  acid  deficiency  already  having  been  found  to  develop  with 
much  greater  rapidity  at  91°  F.  than  at  65°  F. 
Vol.  I.  941 


PHYSIOLOGICAL   CONSIDERATIONS 


467 


Fig.    7  shows  clearly   the   marked   difference   in  optimal  dietary  thia- 
mine level  for  Wistar  rats  kept  in  moist  warmth  and  in  a  cool  environ- 

DIETARY    THIAMINE     AND    GR-OWTH    RATES   IN 
HEAT  AND    COLD 


110 

260- 

250- 

240- 

230- 

220- 

^  210- 

< 

(V  200- 

v_  190- 


qo-91'F 

60%  R.H. 


H   180- 
0    170- 

^  160- 

/   • 

^.50- 
§.40- 
"^    130- 

///' 

120- 

// 

110- 

hy 

100- 

/  ^^^-""^^^ 

90- 

My^^^^^^^^^ 

80- 

V/          ^^"^^--^ 

70  - 

—^ — 1 — I — I    III 

65°  F 


10      17     24     31      38     1-S     52 
DAYS 


3      10     17      24     31     38    45    52 
DAYS 


MOS.    THIAMINE    PER  K.ILO  OF    FOOD 
I   •   0.2       4-  '    08 
2=04       5=1.2 
3  =  06       <o  '■    1.6 
Fig.  8.  Dietary  thiamine  and  growth  rates  in  heat  and  cold. 

ment.     At  91°  F.  food  consumption  is  greatest  in  those  animals  using  a 
diet  containing  1.2  milligrams  of  thiamine  per  kilo,  while  at  lower  levels 
Vol.  I.  941 


468  CLIMATE   IN   HEALTH   AND    DISEASE 

of  dietary  thiamine  there  is  almost  a  quantitative  relationship  between 
food  consumption  and  thiamine  content.  At  65°  F.  on  the  other  hand 
food  consumption  is  sub-optimal  only  at  the  two  lowest  thiamine  levels, 
0.2  and  0.4  milligrams  per  kilo  of  food. 

In  Fig.  8  these  differences  in  dietary  thiamine  requirements  are  brought 
out  even  more  quantitatively  by  differences  in  rate  of  growth.  At  65°  F. 
growth  is  almost  optimal  with  all  the  groups  receiving  0.6  milligrams  or 
more  per  kilo  of  food,  although  the  0.8  milligram  group  was  found  to  do 
best  and  usually  to  show  the  greatest  gain  in  weight  per  gram  of  food 
eaten.  With  rats  kept  at  91°  F.  best  growth  was  obtained  at  the  1.2 
milligram  level  but  with  little  difference  at  1.6  milligrams.  Best  growth 
efficiency,  grams  gain  in  weight  /  grams  of  food  eaten,  was  found  most 
often  at  the  1.6  milligram  thiamine  level  in  the  heat  (90-91°  F.)  but 
at  0.8  milligrams  in  the  cold  (65°  F.)  as  shown  in  the  curves  in 
Fig.  8. 

These  food  consumption  and  growth  differences  at  varying  thiamine 
intake  levels  persist  on  through  to  adult  life,  giving  at  the  lower  thiamine 
levels  the  scrawny,  stunted  specimens  so  similar  to  those  commonly  seen 
among  human  populations  living  under  tropical  lowland  heat.  Many 
students  of  nutritional  problems  have  held  that  a  higher  protein  intake, 
particularly  of  animal  proteins,  would  greatly  improve  the  nutritional 
state  of  tropical  people. 

Higher  cost  of  such  protein  foods  has  prevented  any  widespread  trial 
of  this  idea,  but  unpublished  results  from  the  author's  laboratory  have 
given  indications  that  such  a  step  would  not  be  beneficial  in  tropical 
heat  even  if  it  were  economically  feasible. 

Fig.  9  illustrates  in  striking  fashion  the  handicap  placed  upon 
animals  living  at  91°  F.  when  their  dietary  protein  is  increased  only 
moderately.  The  added  difficulties  in  heat  dissipation  that  result 
from  the  increased  dietary  protein  with  its  higher  specific  dynamic  ac- 
tion seem  just  as  depressive  to  growth  as  do  still  higher  external  tem- 
peratures. 

It  is  unfortunate  indeed  that  the  greater  part  of  our  dietary  supply  of 
vitamin  B  fractions  comes  in  foods  which  are  rich  in  protein,  meats, 
milk  products,  nuts,  legumes.  Cereal  grains  provide  the  only  exceptions, 
and  with  the  two  most  widely  used,  wheat  and  rice,  the  vitamin  stores 
are  largely  removed  in  milling  processes.  Tropical  natives  thus  are  doubly 
handicapped.  Their  need  for  vitamins  of  the  respiratory  catalyst  type  is 
sharply  higher  than  in  cooler  lands,  while  the  principal  foods,  through 
which  they  might  meet  this  higher  need,  are  more  expensive  and  intensify 
their  problem  of  difficulty  in  body  heat  loss.     Fruits  and  starchy  tubers, 

Vol.  I.  941 


PHYSIOLOGICAL   CONSIDERATIONS 


469 


which  supply  such  a  large  part  of  the  tropical  dietaries,  are  low  in  vitamin 
B  fractions  but  can  be  utilized  by  tropical  natives  with  least  intensifica- 
tion of  their  heat  loss  difficulties. 

Man's  higher  requirement  for  the  vitamin  B  fractions  in  tropical 
warmth  probably  plays  an  important  part  in  the  widespread  occurrence 
there  of  such  deficiency  states  as  beri  beri  and  pellagra.  The  subject 
needs  a  thorough  investigation,  for  upon  this  situation  may  hinge  a  con- 
siderable part  of  the  malnutrition  and  low  physical  level  seen  among 
tropical  populations.  The  magnitude  of  the  problem  can  be  appreciated 
only  when  it  is  remembered  that  half  of  the  earth's  human  population 

PROTEIN    INTOLERANCE 
AT  HIGH    TEMPERATURES 


1e  protein  in  diet 
30 


123456789 

TIME     IN    WEEICS 


10        M        a        13        14        IS       M> 


Fig.  9.  Protein  intolerance  at  high  temperatures. 

lives  under  just  such  depressive  heat  as  is  being  discussed  here.  We  can 
as  yet  only  guess  at  the  many  bearings  this  variation  in  vitamin  re- 
quirement at  different  temperature  levels  may  have  in  the  problems  of 
human  welfare.  Since  it  afTects  directly  cellular  combustion  and  the 
source  of  energy  for  all  body  functions,  it  must,  of  necessity,  have  im- 
portant bearings  on  all  the  vital  processes  and  functions  of  the  body.  A 
whole  new  field  seems  to  be  opened  up  by  this  dynamic  view  of  physio- 
logical response  to  climate. 
Vol.  I.  941 


470  CLIMATE   IN   HEALTH   AND   DISEASE 

Climate  and  Disease 

The  preceding  discussion  of  climatic  physiology  provides  a  most  useful 
background  for  an  understanding  of  the  geography  of  many  diseases. 
Tropical  people  with  their  more  sluggish  combustion  rate  and  lowered 
vitality  die  largely  from  the  infectious  diseases;  energetic  residents  of 
cooler  lands  die  more  from  the  breakdown  and  degenerative  diseases. 
Only  with  pneumococcic  and  streptococcic  infections,  largely  respiratory 
or  of  the  nasopharynx,  is  the  attack  frequency  higher  in  temperate  regions 
and  then  only  during  the  seasons  of  great  cyclonic  storminess.  Since 
these  disease  differences  are  based  largely  upon  demonstrable  differences 
in  physiological  response  to  living  environment  and  are  susceptible  to  a 
considerable  degree  of  control,  it  seems  wise  that  the  medical  profession 
consider  them  against  their  proper  physiological  background. 

It  is  not  at  all  surprising  that  clearest  climatic  relationships  should  be 
found  for  the  diseases  of  metabolic  over-stimulation  or  breakdown.  Meta- 
bolic stress  rises  highest  in  middle  temperate  regions,  where  most  nearly 
optimal  heat  loss  conditions  prevail,  while  toward  tropical  warmth  evi- 
dences of  such  stress  progressively  decrease.  Diabetes,  with  its  breakdown 
in  ability  to  metabolize  the  glucose  upon  the  combustion  of  which  de- 
pends all  bodily  energy,  shows  this  climatic  relationship  perhaps  most 
clearly,  but  the  relationship  is  also  quite  evident  for  pernicious  anemia 
with  its  exhaustion  in  the  production  of  red  cells  to  carry  the  oxygen  from 
lungs  to  tissues.  Toxic  goiter  and  hyperthyroidism  seem  likely  to  be  in- 
volved in  this  same  environmental  influence.  Perhaps  most  worrisome  to 
the  medical  profession  of  the  stimulating  regions  are  the  growing  evi- 
dences of  stress  and  failure  in  the  vascular  system.  Upon  this  system 
falls  the  most  direct  load  of  any  tissue  combustion  increase,  for  it  must 
transport  to  the  tissues  all  the  needed  combustion  factors.  The  advance 
of  sudden  heart  failure  toward  earlier  and  earlier  ages  in  American  men 
of  middle  temperate  latitudes  is  presenting  the  medical  profession  with  an 
acute  health  problem  to  consider.  Over  two  thirds  of  the  American 
physicians  dying  in  1939  did  so  from  primary  failure  of  one  sort  or  an- 
other in  the  circulatory  system.  Addison's  disease  with  its  adrenal  failure 
and  other  exhaustion  states  such  as  myesthenia  gravis  and  neurocircula- 
tory asthenia  also  most  frequently  occur  in  these  same  middle  temperate 
latitudes.  And  for  some  reason,  as  yet  little  understood,  it  is  in  these 
same  latitudes  that  cancer  is  presenting  its  greatest  menace  to  man. 
Leukemia,  which  some  consider  to  be  a  form  of  neoplasia,  is  almost  ex- 
clusively a  cool  climate  disease. 

Infectious  diseases  present  the  other  side  of  the  picture,  for  with  them 

Vol.  I.  941 


CLIMATE  AND   DISEASE 


471 


Vol.  I.  941 


472 


CLIMATE  IN  HEALTH  AND   DISEASE 


Vol.  I.  941 


CLIMATE  AND    DISEASE  ■  473 

greatest  frequency  and  highest  death  rates  go  hand  in  hand  with  lowered 
tissue  resistance  in  the  debiUtating  warmth  of  tropical  and  sub-tropical 
regions.  Temperatures  there  are  more  nearly  optimal  for  parasitic  and 
bacterial  contamination  of  water  and  food  supply,  it  is  true,  and  added 
to  this  is  the  tremendous  problem  of  insect  vectors,  but  working  beneath 
these  major  health  threats  in  the  tropics  is  the  lowered  general  tissue 
vitality  from  sluggish  cellular  combustion.  Fig.  10,  showing  regional 
differences  in  the  intensity  of  climatic  stimulation  over  the  earth,  is  pre- 
sented here  so  that  the  reader  may  have  before  him  this  rough  idea  of  the 
metabolic  driving  force  being  exerted  upon  man  in  the  different  regions. 
The  methods  used  in  calculating  the  indices  of  climatic  stimulation  have 
been  described  in  detail  elsewhere'^.  Let  us  see,  in  greater  detail  in  suc- 
ceeding paragraphs  of  this  section,  just  how  important  these  effects  of 
climate  may  be  for  man. 

Diabetes  Mellitus 

With  80  per  cent,  of  the  total  cellular  combustion  being  glucose  burn- 
ing it  is  not  surprising  that  evidences  of  stress  should  appear  in  the  body's 
machinery  for  handling  glucose  under  conditions  that  bring  a  prolonged 
and  sustained  increase  in  tissue  combustion  rate.  No  one  knows  as  yet 
just  what  factors  immediately  determine  which  members  of  a  population 
mass  shall  suffer  this  break  in  glucose  metabolism,  but  the  evidence  is 
convincing  that  the  severity  of  diabetes  as  a  disease  is  strongly  influenced 
in  some  way  by  climatic  stimulation.  While  the  disease  occurs  in  tropical 
people,  it  is  so  mild  as  rarely  to  need  attention  and  seldom  results  in 
severe  ketosis;  mild  dietary  management  usually  is  sufficient  for  complete 
control.  In  the  cooler  and  more  energizing  middle  temperate  latitudes,  on 
the  other  hand,  diabetes  becomes  a  much  more  violent  metabolic  disturb- 
ance with  ketosis  a  frequent  and  real  threat  to  the  patients'  lives  and 
with  eternal  and  painstaking  care  the  price  to  be  paid  for  its  control. 

Fig.  1 1  shows  the  marked  increase  in  recorded  diabetes  mortality 
among  rural  populations  from  the  Gulf  States  northward  in  America  and 
the  decline  on  into  Canada  past  middle  temperate  latitudes.  Failure  of 
the  band  of  high  mortality  rates  to  continue  across  the  upper  Plains  States 
probably  is  due  to  the  younger  average  age  of  the  populations  of  those 
states.  The  disease  is  now  increasing  in  severity  there  as  the  population 
ages,  with  those  states  showing  the  most  marked  rise  in  mortality  rate. 
In  urban  populations  the  age  differences  are  not  so  great  and  in  Fig. 
12  it  is  seen  that  the  band  of  highest  urban  diabetes  mortality  extends 
entirely  across  the  continent. 

Vol.  I.  941 


474 


CLIMATE   IN   HEALTH   AND    DISEASE 


Vol.  I.  941 


CLIMATE  AND   DISEASE  475 

It  is  not  yet  clear  just  why  evidences  of  climatic  stimulation  and  meta- 
bolic stress  should  lessen  on  northward  into  polar  cold  much  like  they  do 
toward  subtropical  warmth.  All  metabolic  and  degenerative  disease  sta- 
tistics do  show  a  decline  in  severity  northward  from  middle  temperate 
latitudes,  and  the  onset  of  the  menses  in  girls  is  progressively  delayed  the 
farther  north  one  goes.  The  reason  may  perhaps  lie  in  the  fact  that  in 
the  milder  winters  of  middle  temperate  regions  people  get  outdoors  more 
and  really  undergo  greater  exposure  to  increased  heat  loss  than  do  people 
living  through  the  prolonged  winter  cold  of  more  northerly  regions.  What- 
ever the  explanation  may  be,  it  does  seem  a  fact  that  human  vitality  rises 
highest  in  middle  temperate  latitudes  both  north  and  south  of  the  equator. 
The  moderating  influence  of  the  Gulf  Stream  on  northwestern  Europe 
seems  to  cause  highest  vitality  there  to  appear  about  15  degrees  farther 
north  than  in  America.  Britain,  northern  France,  Belgium,  the  Nether- 
lands, Denmark,  Germany  and  the  southern  parts  of  Scandinavia  seem 
to  form  the  European  counterpart  of  the  northern  half  of  the  United 
States  in  the  matter  of  climatic  stimulation. 

Fig.  13,  showing  the  ten-fold  increase  in  the  negro  diabetes  death 
rate  from  south  to  north  within  the  United  States,  gives  clear  indication 
of  the  price  this  tropical  race  pays  for  its  higher  energy  level  on  migration 
into  the  stimulation  of  cooler  regions.  Vascular  sclerosis  in  the  negro  is 
also  a  much  more  malignant  disease  in  the  northern  states  than  it  is  in 
the  south,  occurring  with  greater  frequency  and  running  a  more  rapid 
course.  Toxic  goiter  also  becomes  much  more  frequent,  and  pernicious 
anemia  makes  its  appearance  in  a  race  apparently  free  of  the  disease  in 
warmer  regions. 

Fig.  14  shows  the  European  center  of  high  diabetes  mortality  to 
cover  the  same  west-central  European  countries  shown  in  Fig.  10  to  be 
receiving  the  highest  degree  of  climatic  stimulation  available  on  that  con- 
tinent. Statistics  for  either  total  or  urban  death  rates  show  diabetes  in 
this  area  to  be  more  severe  than  in  other  parts  of  the  continent.  In  South 
America  the  disease  becomes  a  health  problem  only  in  the  temperate  cool- 
ness of  Argentina  and  Chile,  while  in  Australia  it  is  of  low  severity  in  the 
north  and  increases  progressively  toward  the  south. 

Diabetes  specialists,  studying  and  handling  the  disease  only  in  the  re- 
gions where  it  is  most  frequent  and  severe,  are  inclined  to  doubt  these 
statistical  indications  of  climatic  or  regional  differences  in  the  disease. 
Less  accurate  diagnosis  and  reporting  of  causes  of  death  they  feel  may 
account  for  most  of  the  differences  in  mortality.  Extensive  surveys  of 
the  disease  in  the  living  populations  of  Massachusetts  and  Arizona,  sum- 
marized in  a  recent  paper  entitled  "The  Universality  of  Diabetes "^^,  was 

Vol.  I.  941 


476 


CLIMATE   IN   HEALTH    AND    DISEASE 


Vol.  I.  941 


CLIMATE  AND   DISEASE 


477 


Vol.  I.  941 


478  CLIMATE   IN    HEALTH   AND    DISEASE 

claimed  to  contradict  the  idea  that  real  differences  do  exist  with  such 
wide  climatic  variation  as  these  two  states  show.  It  is  unfortunate  that 
the  southern  state  chosen  for  comparison  with  Massachusetts  should  have 
been  one  so  heavily  populated  by  former  migrants  from  northern  regions, 
probably  standing  next  to  Florida  and  California  in  this  respect.  But 
even  with  this  high  proportion  of  migrants  from  the  north  the  survey  in- 
dicated a  considerably  lower  diabetes  death  rate  per  i  ,000  cases  in  Arizona 
than  was  found  in  Massachusetts. 

The  evidence  for  climatic  differences  in  diabetes  is  being  discussed  in 
considerable  detail  because  this  disease  has  been  studied  more  thoroughly 
than  have  the  other  metabolic  disturbances,  and  because  it  bears  such  a 
direct  relationship  to  tissue  combustion  rate  and  metabolic  stress.  Then 
too  the  milder  course  followed  by  the  disease  in  warm  climates  is  a  point 
of  great  therapeutic  importance  for  the  people  who  must  live  out  their, 
remaining  life  span  under  its  handicaps. 

Pernicious  Anemia,  Toxic  Goiter  and  Addison's  Disease 

Pernicious  anemia  shows  just  as  clear  evidences  of  climatic  variation 
in  severity  as  does  diabetes.  It  forms  a  real  health  problem  only  in  those 
same  stimulating  temperate  regions  where  diabetes  is  so  severe  and  is  seen 
rarely  in  tropical  warmth.  The  same  holds  true  for  toxic  goiter  and  Addi- 
son's disease.  Higher  death  rates  from  these  metabolic  diseases  in  middle 
temperate  regions  cannot  be  due  only  to  the  reduced  infectious  disease 
death  rates  there  prevailing,  for  there  is  more  frequent  metabolic  break- 
down at  every  age  throughout  life.  Death  rates  for  these  diseases  are 
about  twice  as  high  for  every  age  group  in  northern  LInited  States  as 
for  comparable  populations  along  the  Gulf  of  Mexico.  A  similar  relation- 
ship seems  to  hold  for  other  continents  of  the  earth,  although  lack  of  uni- 
formity in  mortality  records  makes  difficult  so  clear  a  presentation  of  the 
differences  as  is  possible  in  America. 

Arteriosclerosis  and  Heart  Failure 

Arteriosclerosis  and  heart  failure  statistics  are  in  general  still  too  con- 
fused and  lacking  in  uniformity  of  nomenclature  and  diagnostic  criteria 
to  be  of  much  value.  There  seems  little  doubt  that  diseases  of  the  heart 
and  vascular  system  constitute  a  far  more  serious  health  problem  in  tem- 
perate regions  than  in  tropical  warmth.  The  differences  seem  to  be  of 
about  the  same  order  as  with  the  metabolic  diseases.  This  would  be  quite 
in  line  with  expectation,  if  circulatory  failure  is  dependent  upon  stress,  for 

Vol.  I.  941 


CLIMATE  AND    DISEASE 


479 


the  primary  work  load  of  a  higher  tissue  combustion  rate  falls  upon  the 
circulatory  system  as  the  oxygen  carrier.  Although  general  mortality 
statistics  are  unsatisfactory  to  bring  out  this  relationship,  recently  it  has 
been  demonstrated  in  another  way^^  Fig.  15  shows  the  clear  inverse 
relationship  of  non-infectious  heart  failures  to  mean  monthly  temperature 


160 


140 


60 


40 


20 


SMOOTHED  CURVE  OP 
HEART   FAILURE    ONSETS 
(CINCINNATI   1920-38) 


NORMAL  MEAN  TEMP. 
(CINCINNATI   1871-1937> 


(Op) 
80 


70 


40 


30 


•80 


JAM   FEB   MAR   APR   MAY   JUKE  JULY   AUO   SEPT   OCT   NOV   DEC   JAM 

Fig.   15.  Heart  failure  frequency  and  mean  temperature  level. 

level  throughout  the  year  at  Cincinnati,  using  only  fever-free  heart  failure 
admissions  to  the  Cincinnati  General  Hospital  over  a  20-year  period. 
Such  heart  failures  not  only  show  this  striking  seasonal  variation  in  fre- 
quency, but  they  fluctuate  also  with  the  severity  of  the  winter  cold.  Dur- 
ing certain  warmer  Cincinnati  winters  admission  rates  for  such  heart 
failures  were  only  a  quarter  as  high  as  during  winters  of  normal  cold. 
Rheumatic  and  arteriosclerotic  types  of  heart  failure  show  this  relation  to 
prevailing  external  temperatures,  but  not  those  due  to  syphilis. 

Vascular  sclerosis  in  old  age  might  be  expected  in  any  region,  but  it 
seems  that  only  in  the  more  energizing  regions  of  the  earth  do  its  devas- 

VoL.  I.  941 


48o 


CLIMATE   IN   HEALTH   AND    DISEASE 


tating  effects  appear  in  the  earlier  decades  of  life.  Heart  failure  from 
coronary  disease  is  becoming  entirely  too  frequent  in  the  fifth  decade  and 
even  in  the  fourth  in  those  same  energetic  populations  that  are  showing 


Fig.  1 6.  Cancer  death  rates  in  America. 

the  highest  frequency  of  metabolic  breakdown.  Negroes  of  the  north 
show  this  vascular  sclerosis  problem  in  its  most  severe  form,  just  as  they 
suffer  more  severely  from  diabetes.  With  them  sclerosis  is  most  likely  to 
assume  the  malignant,  rapidly  progressive  form.  Negro  deaths  from  ar- 
teriosclerotic (non-syphilitic  and  non-rheumatic)  causes  in  Cincinnati  occur 
Vol.  I.  941 


CLIMATE  AND   DISEASE 


481 


Vol.  I.  941 


482  CLIMATE   IN   HEALTH   AND    DISEASE 

at  significantly  earlier  ages  for  northern-born  negroes  than  for  those  born 
in  the  Gulf  States'^.  Perhaps  the  experimental  studies,  now  being  carried 
on  so  actively  by  various  investigative  groups,  will  throw  valuable  light 
on  this  problem  of  vascular  sclerosis.  Certainly  little  headway  can  yet  be 
claimed  by  the  medical  profession  in  devising  means  for  its  control,  al- 
though it  constitutes  a  really  major  cause  of  disability  and  death  in  popu- 
lations of  temperate  regions. 

Cancer 

Cancer  is  another  major  health  problem  against  the  inroads  of  which 
little  headway  has  yet  been  made.  New  evidence  is  now  being  presented 
to  show  that  here  again  is  a  type  of  disease  showing  the  same  climatic 
relationships  as  do  the  metabolic  disturbances.  All  forms  of  cancer  except 
those  of  the  skin  and  buccal  cavity  are  more  frequent  in  populations  of 
middle  temperate  regions  than  they  are  toward  tropical  warmth^^.  In 
fact  cancer  death  rate  maps  for  any  continent  show  a  remarkable  simi- 
larity to  those  for  diabetes  (see  Figs.  i6  and  17  for  cancer  death  rates  in 
America  and  Europe).  Use  of  death  rates,  however,  is  always  open  to 
the  criticism  that  diagnostic  errors  or  inaccuracy  of  death  certification 
may  mask  the  real  disease  frequency  more  in  some  regions  than  in  others. 
Recent  experimental  proof  has  been  obtained,  though,  strongly  supporting 
the  likelihood  that  there  is  a  real  climatic  factor  in  cancer  production. 

Fig.  18  illustrates  the  marked  suppression  of  cancer  incidence  in 
mice  by  an  environment  of  tropical  warmth.  Virgin  females  of  Little's 
dba  strain  of  cancer  mice,  with  a  normal  breast  carcinoma  incidence  of 
over  50  per  cent.,  were  subjected  to  environmental  temperatures  of  65°  F., 
91°  F.  and  70-75°  F.  With  all  other  factors  of  existence  held  constant 
these  mice  up  to  20  months  of  age  exhibited  practically  a  normal  cancer 
incidence  in  the  room  at  65°  F.,  but  at  91°  F.  there  occurred  a  marked 
suppression.  At  ordinary  laboratory  temperatures,  70-75°  F.,  there  was 
almost  the  same  frequency  as  at  65°  F.  but  with  a  slight  lag  in  time  of 
appearance.  In  addition  to  the  breast  carcinomas,  11  of  these  mice  also 
developed  tumors  of  the  lymphosarcomatous  type  in  internal  organs. 
Five  of  these  were  in  the  group  kept  at  65°  F.,  five  in  the  70-75°  F. 
group  and  only  one  in  those  kept  at  91°  F. 

Tumors  not  only  appeared  less  frequently  and  later  in  the  heat,  but 
their  rate  of  growth  also  was  markedly  slower.  At  91°  F.  they  grew  only 
half  as  rapidly  as  at  65°  F.,  taking  roughly  twice  as  long  to  kill  the  af- 
flicted animal.  This  same  difference  has  been  found  for  chemically- 
induced  and  transplanted  tumors  in  mice  except  for  those  of  the  skin. 

Vol.  I.  941 


CLIMATE  AND    DISEASE 


483 


MUMBBR  OF  MICE  WITH  TUMORS 


la 

S9 


Vol.  I.  941 


484  CLIMATE   IN   HEALTH   AND   DISEASE 

Cancer  masses  grow  most  rapidly  in  the  deeper  tissues  of  mice  kept  in 
the  cold,  but  in  the  heat  they  grow  fastest  in  the  skin.  This  is  an  im- 
portant observation,  for  it  would  seem  to  indicate  richness  of  blood  supply 
to  be  a  dominant  factor.  At  65°  F.  the  deeper  tissues  need  the  richer 
blood  supply  to  support  their  higher  level  of  metabolism,  while  at  91°  F. 
the  difficulty  of  heat  dissipation  calls  for  most  active  circulation  through 
the  cutaneous  capillaries.  If  the  environmental  temperature  be  raised 
sufficiently  to  produce  fever  in  the  mice  and  an  elevation  in  general  metab- 
olism, then  tumors  of  all  regions  grow  more  rapidly  than  in  the  cold. 

The  higher  occurrence  rates  for  skin  cancers  in  people  living  in  warmer 
climates  would  thus  seem  to  be  due  not  to  greater  actinic  irritation  from 
the  tropical  sunlight,  as  has  been  supposed,  but  more  probably  to  the 
richer  cutaneous  blood  supply  for  heat-loss  purposes,  and  in  regions  of 
more  active  stimulation  of  the  general  metabolism  the  higher  incidence 
of  internal  tumors  would  seem  probably  related  to  the  higher  combustion 
rate  and  richer  blood  supply  in  the  deeper  tissues. 

Leukemia 

Leukemia  sometimes  has  been  considered  a  form  of  neoplasia,  so  it  is 
interesting  to  note  that  four  tumor-free  mice  in  the  group  kept  at  65°  F. 
showed  post  mortem  evidences  strongly  suggestive  of  leukemia.  Fig. 
19  also  shows  the  same  band  of  high  leukemia  death  rates  across  middle 
temperate  latitudes  of  North  America  that  was  found  for  cancer  and  the 
metabolic  diseases.  All  in  all,  it  does  seem  that  the  degenerative,  neo- 
plastic and  metabolic  diseases  are  closely  bound  up  in  some  way  with 
general  tissue  combustion  level  and  ease  of  body  heat  loss.  The  thera- 
peutic implications  of  this  relationship  are  many  and  varied,  but  their 
consideration  will  be  taken  up  on  a  later  page. 

Infectious  Diseases 

As  shown  on  an  earlier  page,  resistance  to  infection  and  ability  to  pro- 
duce immune  bodies  seem  closely  linked  to  tissue  combustion  rate  in 
warm-blooded  animals.  Difficulty  in  heat  loss,  enforcing  a  lowering  in 
tissue  heat  production,  causes  a  sharp  decline  in  ability  to  fight  infection. 
This  has  been  shown  to  be  as  true  for  several  infectious  diseases  of  man 
as  for  experimental  infections  in  laboratory  animals.  Thus  one  factor  of 
climate  becomes  of  major  importance  in  infectious  diseases.  There  is, 
however,  a  second  climatic  factor  of  equally  great  importance.  Cyclonic 
storminess,  with  the  atmospheric  changes  that  accompany  passage  over 

Vol.  I.  941 


CLIMATE   AND    DISEASE 


485 


oi 


Vol.  I.  941 


486 


CLIMATE    IN    HEALTH    AND    DISEASE 


a  given  region  of  successive  "highs"  and  "lows",  seems  in  some,  as  yet 
unknown,  manner  related  to  the  initiation  of  infectious  disease  attacks. 
Respiratory  and  rheumatic  infections  are,  perhaps,  most  closely  involved 
in  this  type  of  climatic  effect,  but  it  also  influences  such  other  infectious 
attacks  as  acute  appendicitis  and  puerperal  septicemia. 


AVSEACS  IDNTHLY  FREQUENCY   (1923-1926,    INCXUSIVB)   OF  SPflCIFIKD 
B3SPIBAT0HY  DISEA.SES  CAUSING  DISABILITY  POIl  ONiS  DAY  OH  LOUG^ 
ALIOKC  ABOUT  3,000  E12L0YS3S   OF  THi:  SDISON  3LSC?HIC  ILLUIIIIIATIHG 
COLPAinC  OF  BOSTON  • 


Jul.  Auc.   Sept.   Oct.Nov.Dec.   Jan.  .Fe'b.  l".:>x..  Apr.  liiy  .Jun. 
r        I     ^   I     ^  I H-_|I 1 1 • 


1^  r^i 


\a3 


Jul.   Aug. Sept. Oct.   Nov.  Dec.   Jan. Fe'b.  l!ar.   Apr.lAy    'JUn. 
tonth  In  Which  Dioability  Began 


Atout   twenty  per  cent  of   the    total  number  of  persons  included 
In  tikis  record  were  women. 

Fig.  20.   Seasonal  variations  in  respiratory  illness. 

Fig.  20  illustrates  the  striking  degree  to  which  respiratory  infections 
are  associated  with  winter  cold  and  storminess  in  north  temperate  lati- 
tudes. Life  hazards  of  all  sorts  reach  a  peak  at  this  season,  for  to  the 
infectious  dangers  of  the  more  violent  storminess  is  added  the  greater 
stress  of  an  increased  metabolic  load.     In  southern  hemisphere  lands  win- 

V'oi,.  I.  941 


CLIMATE  AND   DISEASE  487 

ter  brings  much  less  of  an  increase  in  life's  hazards,  for  there  stormi- 
ness  is  least  during  mid-winter  cold.  The  increase  in  mortality  from 
respiratory  infections  in  the  United  States,  from  summer  low  to  mid- 
winter high,  is  almost  three  times  as  great  as  it  is  in  similar  latitudes  of 
Australia.  And  in  the  United  States  unusually  stormy  winters  are  ac- 
companied by  much  greater  frequency  of  respiratory  illness  and  death 
than  are  those  of  lesser  atmospheric  turbulence.  Hospital  admissions  for 
acute  rheumatic  fever  at  Cincinnati  show  a  similar  parallelism  with  sea- 
sonal changes  in  storminess. 

This  relationship  of  storminess  to  infections  is  just  as  evident  on  a 
regional  as  on  a  seasonal  basis.  Acute  respiratory  infections  and  acute 
rheumatic  fever  are  predominantly  diseases  of  stormy  regions,  being  worst 
in  the  middle  temperate  belt  of  cyclonic  storms  and  least  troublesome  in 
calm  tropical  warmth.  Respiratory  disease  in  the  tropics  becomes  a  real 
problem  only  in  those  regions  afflicted  with  cyclonic  storms  of  the  typhoon 
or  hurricane  type.  Such  regions  include  most  of  the  Philippine  Islands 
and  the  eastern  Asiatic  coast  up  to  Japan,  those  parts  of  India  around 
the  Bay  of  Bengal,  most  of  the  West  Indies  and  nearby  eastern  seaboard 
of  North  America  and  to  a  lesser  degree  the  southwestern  coastal  region 
of  Mexico.  Low  pressure  storm  centers  passing  over  these  regions  seem 
to  bring  much  the  same  respiratory  disease  problems  as  are  faced  by  peo- 
ple living  in  the  temperate  zone  storm  belts.  They  do  not  have  the  body 
chilling  from  sudden  temperature  change,  such  as  afflicts  people  of  stormy 
temperate  regions,  but  the  pressure  changes  alone  seem  capable  of  initiat- 
ing the  infectious  attacks.  Careful  physiological  studies  are  badly  needed 
in  this  field  of  pressure-change  effects,  particularly  as  regards  disturbances 
in  tissue  water  balance.  Present  knowledge  in  this  field  is  extremely 
sketchy  and  inadequate. 

In  order  to  give  a  general  appreciation  of  the  storm  problem  over 
North  America,  there  is  shown  in  Figs.  21  and  22  the  course  followed 
by  anti-cyclonic  high-pressure  centers  affecting  the  United  States  during 
the  four-year  period,  1926-29.  Each  such  major  "high"  center  affects  an 
area  1,500  to  2,000  miles  in  diameter,  as  it  sweeps  across  the  continent. 
From  these  figures  one  may  get  some  idea  of  the  relative  differences  in 
storm  effects  man  faces  in  different  parts  of  the  continent  during  the 
winter  and  the  total  reduction  in  storminess  that  comes  with  summer 
warmth.  In  the  summer  storm  centers  cross  the  continent  less  frequently, 
travel  more  slowly  and  are  accompanied  by  less  abrupt  and  less  ex- 
tensive atmospheric  changes.  At  no  time  of  the  year  do  major  storm 
centers  cross  the  southwestern  part  of  the  United  States  or  the  highland 
regions  of  Mexico.     This  non-stormy  zone  expands  northeastward  during 

Vol.  I.  941 


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Vol.  I.  941 


CLIMATE  AND    DISEASE 


493 


summer  warmth,  and  at  this  season  people  of  the  Old  South  are  left  with 
the  stagnant,  moist  heat  typical  of  tropical  regions.  These  two  storm 
maps  deserve  considerable  study,  for  from  them  can  be  obtained  much  of 
the   storm-health    story.      Figs.  23   and  24,  depicting   the  daily  tempera- 


FlG.  26.  Acute    appendicitis    cases    hospitalized    in    certain    American    cities,    annual 
average,  (1928-32). 

ture  changes  through  the  year  at  Charleston  and  at  Bismarck,  give  strik- 
ing emphasis  to  the  differences  in  atmospheric  change  that  these  storm 
centers  bring  to  the  various  regions  over  which  they  pass.  Fig.  25 
shows,  for  contrast,  the  daily  temperature  behavior  in  a  non-stormy 
Vol.  I.  941 


494  CLIMATE   IN   HEALTH   AND    DISEASE 

tropical  region  with  its  endless  monotony  of  successive  days  of  depressive 
moist  heat. 

It  is  in  the  stormy  winter  season   and   in   the  stormy  regions  of  the 
earth  that  respiratory  and  rheumatic  infections  most  severely  afiflict  man- 


FiG.  27.  Acute  appendicitis  deaths  per  100  cases  in  certain  cities. 

kind.  Benefits  of  migration  of  individuals  from  such  regions  to  non-stormy 
areas  will  be  discussed  in  the  next  section  which  deals  in  some  detail  with 
climatic  therapy  in  relation  to  various  disease  conditions  from  which  man 
suffers. 

Vol.  I.  941 


CLIMATE  AND   DISEASE  495 

Acute  Appendicitis 

Acute  appendicitis  statistics,  obtained  in  a  limited  survey  of  25  Ameri- 
can cities^^,  illustrate  well  the  possible  relationships  that  might  be  found 
between  climatic  characteristics  and  infectious  diseases,  if  morbidity  sta- 
tistics were  more  generally  available.  Fig.  26  hints  strongly  at  a  storm 
distribution  of  the  acute  appendicitis  attacks  with  highest  rates  down  the 
western  plains  along  the  major  storm  pathway  from  the  Canadian  North- 
west. It  is  in  this  area  that  appendicitis  becomes  a  rapidly  fulminating 
disease  with  quick  progress  to  perforation  and  spreading  peritonitis,  if  not 
promptly  operated  upon.  Nowhere  else  in  temperate  regions  is  it  so  fre- 
quent or  severe.  Only  in  the  worst  storm-ridden  parts  of  the  Philippines 
and  West  Indies  does  it  compare  in  frequency  of  attacks  with  this  central 
trough  of  North  America.  In  non-stormy  regions,  either  tropical  or  tem- 
perate, it  is  a  much  less  virulent  and  less  frequent  disease.  Its  relation- 
ship to  storminess  can  be  shown  at  any  given  point  by  its  tendency  to 
occur  as  waves  or  epidemics  of  attacks  with  the  approach  or  passing  of 
each  low-pressure  center  and  by  the  sharp  reduction  in  attack  frequency 
as  high  pressure  areas  come  along. 

Regional  differences  in  ability  to  survive  such  infectious  attacks  are 
well  illustrated  in  Fig.  27,  showing  the  steady  fall  in  fatality  rate  per 
100  attacks  from  the  Gulf  States  northward.  Here  it  is  the  greater  ease 
of  body  heat  loss  and  more  active  tissue  combustion  in  the  north  that 
brings  on  better  resistance  to  the  infectious  attacks.  The  fatality  rate 
mounts  with  summer  heat  even  in  those  cooler  latitudes  where  general 
resistance  to  infection  is  highest. 

Acute  Nephritis 

Acute  nephritis  is  another  infectious  disease  in  which  clear  climatic 
relationships  can  be  demonstrated.  In  both  Europe  and  America  (Figs. 
28  and  29)  it  causes  fewest  deaths  in  regions  of  highest  climatic  stimula- 
tion, while  towards  either  tropical  warmth  or  polar  cold  its  death  rate 
rises.  In  the  depressing  moist  heat  of  tropical  lowlands  it  becomes  a 
really  important  cause  of  death. 

Heat  Stroke,  Heat  Exhaustion  and  Heat  Cramps 

In  addition  to  the  profound  effects  upon  tissue  combustion  rate  and 
body  functions  exerted  by  moderate  difficulties  in  heat  dissipation,  there 
are  also  more  acute  disturbances   brought   by  excessively  high   environ- 

VoL.  I.  941 


496 


CLIMATE   IN   HEALTH   AND    DISEASE 


mental  temperatures.     Such  disturbances  are   predominantly  problems  of 
human  populations  living  in  the  middle  temperate  latitudes.     This  is  true 


Fig.  28.  Acute  nephritis  death  rate  per  100,000  estimated  population,  U.  S.  A.  1924-8 
incl.,  Canada  1923-7  inch,  white  race  only. 


for  two  reasons,  both   of  which  are  involved  in  an  explanation  of  the 
physiology  of  these  excessive  heat  effects. 

The  first  reason  for  greatest  prevalence  of  acute  heat  effects  in  tem- 

V'oL.  I.  941 


CLIMATE  AND   DISEASE 


497 


Vol.  I.  941 


498  CLIMATE   IN   HEALTH   AND   DISEASE 

perate  regions  is  that  there  man's  own  internal  heat  production  is  highest 
and  his  necessity  for  rapid  heat  dissipation  greatest.  Animal  studies^i 
under  controlled  conditions  have  provided  a  satisfactory  explanation  for 
heat  sensitivity  in  man.  Either  animals  or  men  adapted  for  weeks  or 
months  to  cool  surroundings  develop  a  high  combustion  rate,  and  this 
proves  embarrassing  when  sudden  difficulty  in  heat  loss  is  encountered. 
In  regions  afflicted  with  depressing  tropical  moist  heat  these  acute  heat 
effects  are  uncommon.  People  residing  there  have  adapted  themselves  to 
a  lower  rate  of  internal  heat  production,  and  acute  effects  are  seldom  seen 
except  in  newcomers  from  cooler  regions.  It  is  in  the  more  energetic 
population  masses  of  middle  temperate  latitudes  that  acute  heat  effects 
occur  in  greatest  profusion.  Severe  heat  waves  of  summer  come  upon 
these  regions,  suddenly,  and  sometimes  kill  thousands  of  people  before 
their  body  heat  production  can  be  brought  down  within  their  capacity 
for  dissipation  under  the  difficult  conditions  suddenly  prevailing.  Partic- 
ularly prone  to  this  embarrassment  from  the  sudden  heat  are  the  less  re- 
silient sclerotic  patients  and  those  of  limited  cardiac  capacity.  Increased 
peripheral  circulation  to  facilitate  the  loss  of  internal  heat  throws  a  greater 
burden  upon  the  heart,  hence  the  heat  wave  dangers  for  those  with  heart 
trouble. 

Animal  and  human  studies  have  shown  that  lo  days  to  2  weeks  are 
required  for  any  considerable  subsidence  of  basic  internal  combustion  in 
response  to  external  heat.  Population  masses  demonstrate  this  delay  in 
adaptation  by  being  able  to  stand  considerably  more  severe  heat  in  August 
than  could  be  safely  borne  in  June  or  early  July.  In  fact,  most  heat  stroke 
epidemics  occur  in  early  July  rather  than  in  the  hotter  weather  of  August. 
But  if  a  severe  July  heat  wave  were  to  be  inflicted  upon  these  same  popu- 
lations at  the  height  of  their  winter  activity,  its  effects  would  be  truly 
devastating,  perhaps  as  much  so  as  would  a  North  Dakota  winter,  if 
suddenly  inflicted  upon  the  people  of  Manila  or  Singapore  or  Calcutta, 
It  is,  then,  the  prevailing  internal  heat  production  rate  of  man  that  largely 
determines  his  sensitivity  to  acute  heat  effects  when  faced  suddenly  with 
severe  external  warmth. 

The  second  factor  responsible  for  the  greater  prevalence  of  acute  heat 
effects  in  temperate  latitudes  is  that  most  severe  heat  actually  occurs 
there.  Dry  bulb  temperatures  of  over  100°  F.  are  rare  in  tropical  regions 
except  in  desert  areas,  while  temperatures  above  this  level  are  not  unusual 
during  severe  summer  heat  waves  as  far  north  as  the  prairie  provinces  of 
Canada.  Heat  deaths  and  prostration  occur  mostly  in  urban  and  desert 
regions  and  for  somewhat  similar  regions.  With  the  dense  vegetation  of 
tropical  lowlands,  and  less  so  in  rural  temperate  areas,  the  physical  sur- 
VoL.  I.  941 


CLIMATE  AND   DISEASE  499 

roundings  of  man  have  a  high  water  content.  Green  foliage  is  largely 
water,  and  the  high  specific  heat  capacity  of  water  enables  it  to  absorb 
large  amounts  of  radiant  heat  from  the  daytime  sun  with  little  rise  in 
temperature.  Baked  earth,  desert  sands  and  urban  building  or  paving 
materials  have  a  very  low  specific  heat  capacity  and  sufifer  a  marked 
temperature  rise  under  the  radiant  heat  load  from  the  sun.  In  desert 
regions  this  daytime  heat  is  quickly  re-radiated  off  into  space  soon  after 
sundown,  but  in  built-up  urban  areas  it  tends  to  be  trapped  within  build- 
ings and  to  cause  progressively  higher  temperatures  as  the  heat  wave 
persists  day  after  day.  Building  construction  in  tropical  cities  takes  ac- 
count of  this  danger  and  provides  for  ample  air  currents  to  carry  away 
any  such  daytime  heat  that  gains  access,  but  in  temperate  zone  cities 
winter  cold  prohibits  this  open  type  of  construction,  and  the  trapping  of 
daytime  radiant  heat  makes  the  heat  problem  for  urban  dwellers  worse 
with  each  added  day  of  summer  heat  wave. 

The  exact  mechanism  of  heat  stroke  production  is  not  understood. 
Patients  in  a  hypertherm  chamber  develop  artificial  fever  but  with  free 
perspiration  and  without  the  other  evidences  of  heat  stroke.  In  typical 
heat  stroke,  on  the  other  hand,  cessation  of  perspiration  seems  to  be  one 
of  the  very  early  symptoms  of  trouble.  Sufficiently  severe  heat  will  kill 
anyone,  normal  and  abnormal  alike,  but  it  may  well  be  that  the  previously 
normal  individual  would  continue  free  perspiration  to  the  end,  while  the 
abnormally  heat  sensitive  person  is  so  because  his  sweating  mechanism 
quickly  becomes  deranged.  Chief  difficulty  in  studying  this  problem  is 
the  lack  of  experimental  animals  with  a  sweating  mechanism  at  all 
similar  to  that  of  man.  Artificial  fever  treatments  on  man  have  provided 
some  valuable  evidence,  but  even  this  has  not  been  well  utilized  to 
elucidate  the  heat  stroke  mechanism.  Patients  who  fail  to  perspire 
freely  under  such  treatment  are  removed  quickly  as  poor  risks  for  fever 
therapy. 

Heat  exhaustion,  while  still  a  direct  result  of  difficulty  in  dissipation  of 
body  heat,  differs  sharply  from  heat  stroke.  In  the  latter  there  is  fever 
and  delirium  with  full  bounding  pulse  and  elevated  blood  pressure,  while 
the  skin  is  flushed  and  dry.  Immediately  important  in  therapy  is  rapid 
heat  removal  by  the  best  means  at  hand.  Heat  exhaustion,  on  the  other 
hand,  usually  is  characterized  by  subnormal  body  temperature,  cold,  pale, 
clammy  skin,  low  blood  pressure  and  a  state  of  circulatory  shock.  In 
addition  there  are  other  symptoms  of  acute  adrenal  insufficiency,  hyper- 
tonicity  of  the  gastroenteric  tract  with  nausea,  vomiting,  diarrhea,  sphinc- 
ter spasm  and  painful  peristalsis.  Here  immediate  treatment  should  be 
directed  toward  raising  the  body  temperature  to  normal,  improving  the 

Vol.  I.  941 


500  CLIMATE    IN    HEALTH   AND    DISEASE 

tone  of  the  vascular  system  and  allaying  hyperactivity  in  the  digestive 
musculature. 

It  is  thus  apparent  that  heat  stroke  and  heat  exhaustion  represent 
radically  different  body  responses  to  external  warmth.  Correct  diagnosis 
is  important  because  of  the  sharp  difference  in  type  of  treatment  indicated. 
Here  again  we  are  faced  by  a  lack  of  knowledge  as  to  why  one  individual 
develops  the  dynamic  hyperpyrexia  response  and  another  the  hypothermic 
shock  reaction.  Unfortunately,  one  experience  with  either  type  of  exces- 
sive heat  reaction  predisposes  the  patient  to  subsequent  attacks  and  to 
troublesome  prodromal  symptoms  with  external  heat  of  relatively  low 
order.  So  far  no  means  has  been  discovered  for  overcoming  this  increased 
sensitivity  induced  by  a  preceding  heat  attack.  Careful  avoidance  of  ex- 
posure for  the  next  several  years  remains  the  patient's  only  safe  course  to 
follow. 

There  exists  a  likely  possibility  that  pantothenic  acid  deficiency  may 
be  a  factor  in  the  production  of  heat  exhaustion.  The  symptoms  and  ana- 
tomical findings  in  heat  exhaustion  point  to  the  adrenal  cortex  as  the  af- 
fected tissue  responsible  for  the  exhaustion  state.  Adrenal  hemorrhage  in 
man  gives  much  the  same  clinical  picture,  except  that  it  is  in  more  acute 
form.  In  experimental  animals,  exposed  to  heat  in  the  author's  labora- 
tory, adrenal  hemorrhages  were  produced  in  few  instances,  but  intense 
adrenal  congestion  was  encountered  frequently.  Recent  work'^'  ^^  has  shown 
that  such  congestion  and  hemorrhagic  necrosis  of  the  adrenals  is  pathogno- 
monic of  pantothenic  acid  deficiency  in  animals,  while  such  deficiency  signs 
have  been  found  much  more  easily  produced  in  animals  kept  at  high  tem- 
peratures in  the  author's  laboratory.  The  possibility  does,  therefore,  exist 
that  heat  exhaustion  with  its  attendant  symptoms  of  adrenal  failure  may 
be  based  upon  a  pantothenic  acid  deficiency,  and  that  the  administration 
of  this  material  would  provide  a  useful  therapeutic  aid  in  the  treatment 
of  such  exhaustion.  The  severe  heat  of  coming  summers  will  give  an  op- 
portunity for  trial  of  such  therapy.  Thiamine  therapy,  5-10  mgm.  daily, 
also  seems  to  make  for  better  heat  resistance. 

Heat  cramps  in  the  skeletal  muscles  bear  little  relation  either  to  heat 
stroke  or  heat  exhaustion.  They  are  due  primarily  to  excessive  salt  loss 
during  profuse  and  prolonged  perspiration  without  adequate  salt  intake. 
Relief  is  obtained  readily  by  adding  ordinary  table  salt  to  the  drinking 
water  or  by  taking  it  in  any  other  convenient  form.  Sometimes  a  heat 
exhaustion  patient  will  be  suffering  also  from  skeletal  muscle  cramps,  but 
usually  they  are  not  associated.  Laborers  in  desert  heat  and  furnace 
rooms  are  particularly  prone  to  heat  cramps  because  of  their  excessive 
perspiration  and  rapid  salt  loss. 
Vol.  I.  941 


CLIMATE   AND    DISEASE  500  (i) 

Sickness  and  Health  Tides 

An  important  point  of  general  medical  interest  arises  from  the  close 
association  between  temperature  level  and  storminess  on  the  one  hand  and 
infectious  illnesses  and  metabolic  breakdown  on  the  other  as  set  forth  in 
the  preceding  pages.  Definite  health  tides  have  been  found^''  to  accompany 
the  periods  of  warmth  and  calm  that  come  over  the  world  every  few 
years.  At  these  times  earth  temperatures  rise,  and  temperate  zone  stormi- 
ness lessens.  Winter  stress  is  reduced  greatly  and  summer  heat  increases. 
Human  energy  seems  to  decline  during  such  years  of  warmth,  for  business 
activity  falls  off,  and  the  economic  machine  tends  to  idle  along  until  cold 
and  storms  again  return.  This  relationship  between  earth  weather  and 
economic  activity  seems  to  be  a  true  finding.  More  striking  from  a 
medical  point  of  view,  however,  is  the  health  improvement,  which  regu- 
larly comes  with  these  years  of  warmth  and  lessened  economic  activity. 
Huntington-^  first  pointed  out  this  association  between  improved  health 
and  hard  times,  but  Huntington's  explanation  of  the  relationship  is  no 
longer  tenable. 

Sickness  and  death  rates  do  decline,  and  calls  for  medical  service  are 
lessened  during  years  of  warmth  and  lessened  storminess,  and,  as  falling 
temperatures  bring  increased  mass  energy  and  returning  prosperity,  we 
regularly  see  again  a  rising  ill-health  tide.  These  tides  in  energy  and 
health  are  similar  to  the  seasonal  ones  which  occur  in  temperate  regions, 
where  winter  cold  and  storms  regularly  bring  greater  energy  but  also 
bring  higher  sickness  rates  and  death  rates.  Even  heart  failures,  non- 
infectious, non-luetic,  reflect  in  their  course  the  lessened  stress  of  these 
warmer  years. 

While  there  is  little  we  can  do  about  these  tides  in  weather  and  health, 
it  is  well  to  appreciate  their  presence  and  significance.  Periods  of  eco- 
nomic depression  commonly  are  associated  with  an  expectation  of  deterio- 
ration in  health  and  general  nutrition  of  the  population.  Even  a  regula? 
repetition  of  health  improvement  in  hard  times,  instead  of  health  de- 
terioration, has  failed  to  shake  the  popular  expectation.  It  is  time  the 
medical  profession  awakened  to  the  fact  that  general  health  is  best  in 
those  very  years  when  the  public  is  willing  to  spend  least  for  medical 
services.  It  is  not,  however,  that  the  services  of  the  medical  profession 
constitute  a  health  handicap,  but  that  powerful  extraneous  forces  are  at 
work  altering  the  basic  environmental  factors  of  existence.  Careful 
analysis  of  the  action  of  these  tidal  forces  on  health  has  helped  us  toward 
a  much  clearer  understanding  of  how  environmental  factors  produce  their 
effects. 

Vol.  I.  941 


5oo(2)  CLIMATE    IN   HEALTH   AND   DISEASE 

Climatic  Therapy 

Two  cardinal  features  of  climatic  effects  must  be  kept  in  mind  when 
climatic  therapy  is  being  considered.  Probably  of  greatest  importance  to 
man  in  a  given  region  is  the  mean  temperature  level  and  the  ease  with 
which  he  can  get  rid  of  his  waste  heat  of  cellular  combustion.  Proper 
ease  of  heat  loss  gives  to  human  health  a  more  dynamic  and  positive 
character,  leading  to  rapid  growth,  early  maturity,  high  fertility,  increased 
resistance  to  infection  and  abundant  energy  for  thought  and  action,  but 
with  the  heightened  cellular  combustion  rate  necessary  to  support  this 
more  dynamic  existence  go  evidences  of  stress  and  breakdown  in  the  body 
machinery.  Metabolic  and  degenerative  diseases  form  the  most  trouble- 
some health  problems  only  in  those  regions  where  climatic  stimulation  is 
high. 

With  the  slower  combustion  rate,  necessitated  by  tropical  difficulties  in 
heat  loss,  existence  becomes  more  vegetative  and  passive,  growth  and  de- 
velopment slow  down,  and  a  sharp  decline  in  resistance  to  infection  allows 
infectious  diseases  to  become  predominant  causes  of  death.  Factors  out- 
side of  man  himself  also  contribute  largely  to  the  infectious  disease 
problem  in  tropical  warmth,  especially  better  temperature  conditions  for 
the  growth  of  bacteria  and  parasites  outside  the  body  and  the  greater 
abundance  of  insect  vectors.  Other  important  factors,  while  not  having 
to  do  directly  with  lowered  tissue  resistance,  do  depend  upon  man's 
lowered  combustion  rate  and  lack  of  energy  for  thought  and  for  work 
accomplishment.  The  low  level  of  personal  and  public  hygiene  usually 
existing  among  tropical  peoples,  unless  health  measures  are  initiated  and 
enforced  by  outsiders  from  more  energizing  climates,  most  likely  is  based 
upon  the  debilitating  effects  of  the  tropical  warmth  upon  man  himself. 
The  combination  of  all  these  internal  and  external  effects  of  climate  makes 
the  infectious  disease  problem  the  major  one  for  tropical  residents. 
People  of  warmer  regions,  who  survive  infectious  hazards  to  reach  more 
advanced  ages,  do  so  with  much  less  evidence  of  metabolic  stress  than  is 
seen  in  similar  age  groups  of  more  stimulating  regions.  Metabolic  and 
degenerative  diseases,  diabetes,  toxic  goiter,  pernicious  anemia,  arterio- 
sclerosis, cancer,  are  all  much  less  prevalent  in  Gulf  State  populations  than 
in  the  same  age  groups  in  middle  temperate  latitudes  of  America.  Similar 
latitude  differences  are  to  be  found  in  Europe. 

The  second  climatic  factor  to  be  considered  in  any  intelligent  effort 
to  use  climatic  therapy  is  the  effect  of  storminess  or  sudden  weather 
change.  Although  we  as  yet  know  little  about  the  mechanism  of  its 
effects,  weather  change  does  seem  to  be  an  important  factor  in  the  initi- 

VOL.  I.    941 


CLIMATIC   THERAPY  500(3) 

ation  of  many  types  of  infectious  attacks,  particularly  those  of  respiratory 
and  rheumatic  types.  Since  respiratory  and  rheumatic  ailments  bulk  so 
large  as  ill  health  factors  in  stormy  regions,  it  is  necessary  that  this 
storminess  factor  be  given  proper  consideration.  _       _ 

These  are  the  general  principles  to  be  borne  in  mind  when  considenng 
climatic  therapy  for  individual  cases.  Physicians  should  help  the  patient 
come  to  a  decision  regarding  permanent  change  of  residence.  For  most 
adult  people  such  re-location  entails  major  economic  difficulties,  which 
tend  to  tie  the  individual  to  his  present  place  of  abode.  It  is  the  physi- 
cian's duty,  then,  to  help  him  balance  the  anticipated  health  benefits 
against  the  deterring  economic  factors.  For  younger  patients  not  yet 
tied  down,  the  problem  is  much  more  simple.  But  in  every  case  it  is  for 
the  physician  to  point  out  the  anticipated  health  hazards  and  impair- 
ments in  body  function  that  may,  reasonably,  be  expected  from  continu- 
ing on  in  the  unfavorable  environment  and  to  detail  the  health  advantages 
of  the  change.  Each  case  will  offer  an  entirely  different  set  of  difficulties 
and  problems  to  be  considered.  And  always  in  these  considerations  the 
physician  should  take  an  active  and  sympathetic  part  as  family  advisor. 
Let  us  now  take  up  in  some  detail  the  facts  upon  which  his  advice  should 
be  based  in  various  disease  states. 

Metabolic  Diseases 

Fairly  clear  indications  of  benefit  from  climatic  therapy  exist  in  the 
diseases  of  metabolic  exhaustion  or  over-stimulation.  Diabetes  as  a  disease 
is  most  frequent  and  most  severe  in  the  energizing  middle  temperate 
regions  where  metabolic  stress  is  greatest.  There  severe  ketosis  and 
coma  are  of  easy  occurrence  and  constitute  major  hazards  for  these  pa- 
tients. The  disease  exists  in  sub-tropical  and  tropical  lands  but  as  a 
mild,  non-troublesome  glycosuria  with  little  or  no  tendency  to  severe 
ketosis.  Mild  dietary  regulation  usually  suffices  for  the  needed  degree  of 
control.  Vascular  troubles  and  peripheral  gangrene  bother  diabetic  pa- 
tients much  more  in  the  cooler  regions,  where  arteriosclerotic  troubles  are 
more  common,  and  winter  cold  further  intensifies  this  hazard  of  the  dis- 
ease. It  seems  clear,  therefore,  that  diabetic  patients  should  be  advised  of 
the  milder  course  taken  by  their  disease  in  warmer  regions.  Permanent 
migration  into  subtropical  warmth  should  be  advised  whenever  it  is 
economically  possible  for  the  patient.  The  strong  tendency  of  the  disease 
to  appear  in  children  of  diabetic  parents  makes  such  migration  particu- 
larly advisable  where  there  are  offspring  to  be  considered. 

Migration  for  diabetics  should  consider  not  only  transfer  to  subtropical 
Vol.  I.  941 


500(4)  CLIMATE   IN   HEALTH   AND    DISEASE 

warmth  but  also  escape  from  cyclonic  storminess.  Acute  infectious  at- 
tacks form  the  most  frequent  cause  for  ketosis  onset  in  these  patients,  and 
cyclonic  storm  changes  seem  to  be  a  potent  factor  in  the  initiation  of  the 
infections.  Migration  should  therefore  be  to  a  non-stormy  and  warm 
region.  In  North  America  that  would  mean  the  Southwest  within  200 
miles  of  the  Mexican  border  from  El  Paso  to  the  Pacific  coast.  Altitudes 
above  5,000  feet  should  be  avoided  because  of  the  relief  from  the  summer 
heat  such  elevation  brings  and  the  fair  degree  of  metabolic  stimulation 
brought  by  the  wide  diurnal  changes  in  temperature.  Florida  and  the 
Gulf  Coast  offer  more  depressing  warmth  than  does  the  Southwest,  due  to 
the  higher  humidity  of  the  air,  but  winter  storminess  and  the  attendant 
respiratory  infection  problem  there  presents  a  certain  degree  of  handicap, 
except  in  the  southernmost  parts  of  Florida  and  Texas. 

European  diabetics,  mostly  to  be  found  living  in  west  central  portions 
of  the  continent,  would  find  their  disease  much  less  troublesome  and  easier 
of  control,  if  they  took  up  residence  in  some  Mediterranean  location.  In 
Australia  benefit  would  follow  northward  migration  to  more  tropical  por- 
tions of  the  continent.  In  Argentina  similar  northward  migration  would 
benefit  those  diabetics  from  the  southern  cool  half  of  the  country,  where 
the  disease  is  more  frequent  and  troublesome. 

Seasonal  migration  away  from  winter  cold  and  storms  is  advisable  for 
those  diabetics  who  cannot  make  a  permanent  change  of  residence,  but  in 
such  seasonal  migration  the  dangers  of  too  early  return  in  the  spring 
should  always  be  kept  clearly  in  mind.  This  point  will  be  discussed  more 
fully  in  considering  respiratory  disease  problems. 

Toxic  Goiter  and  Hyperthyroid  States 

Toxic  goiter  and  other  hyperthyroid  types  of  patients,  except  those  with 
definite  nodular  goiter,  benefit  greatly  from  migration  into  the  depressing 
warmth  of  the  tropics  or  subtropics.  Even  the  brief  summer  heat  of 
northern  latitudes  tends  to  quiet  down  the  symptoms  resulting  from  a 
hyperactive  thyroid.  Definite  microscopic  evidence  of  change  toward  the 
resting  type  of  secreting  cell  has  been  shown  to  result  from  even  a  few 
weeks'  exposure  of  experimental  animals  to  external  warmth.  Hyper- 
thyroid patients  should  not  expose  themselves  too  suddenly  to  external 
heat,  however,  for  their  high  rate  of  heat  production  renders  them  unduly 
susceptible  to  thermic  fever.  Application  of  gradually  increasing  external 
warmth  gives  best  results.  Since  storminess  makes  little  difference  to 
these  patients,  and  a  maximal  depression  of  internal  combustion  rate  is 
desired,   migration   should   be   to  regions  where  heat  and  high   humidity 

Vol.  I.  941 


CLIMATIC   THERAPY  500(5) 

coincide.  In  America  that  would  mean  the  Gulf  Coast,  well  south  in 
Florida  or  Texas  for  the  winter  season.  Artificial,  moist  warmth,  if  con- 
sistently and  properly  applied,  should  be  just  as  effective  in  the  patient's 
own  home  region,  but  it  would  necessitate  an  indoor  existence  for  a  con- 
siderable period  at  high  temperatures  and  high  humidity,  90°  F.  and  70 
per  cent,  relative  humidity  or  thereabouts. 

Pernicious  Anemia 

Pernicious  anemia  likewise  pursues  a  milder  course  in  tropical  warmth, 
while  leukemia  is  almost  unknown  in  tropical  and  subtropical  warmth 
except  in  migrants  from  temperate  climates.  There  are  as  yet  no  data 
available,  however,  regarding  the  benefits  of  climatic  therapy  in  these 
conditions.  For  those,  who  can  move,  either  seasonal  or  permanent 
migration  to  avoid  winter  cold  would  seem  advisable.  As  with  diabetes 
and  toxic  goiter  regions  of  moist  heat  should  be  chosen  so  as  to  achieve 
the  maximum  of  metabolic  suppression  and  reduction  in  load  on  the 
hemopoietic  system. 

Arteriosclerosis,  Hypertension  and  Heart  Failure 

Arteriosclerotic,  hypertensive  and  heart  failure  patients  present  the 
clearest  likelihood  of  benefit  from  climatic  therapy.  Blood  pressures  in 
either  normal  or  hypertensive  individuals  show  a  decided  tendency  to  drop 
with  even  the  brief  summer  heat  of  middle  temperate  latitudes.  This 
drop  usually  amounts  to  about  30  per  cent,  from  the  preceding  winter 
level,  giving  marked  relief  from  hypertensive  symptoms  during  summer 
and  early  autumn.  Both  systolic  and  diastolic  pressures  of  the  author 
fall  about  40  per  cent,  after  a  month  spent  in  tropical  moist  heat  or  after 
a  prolonged  summer  heat  wave  at  Cincinnati.  These  falls  in  pressure 
probably  are  due  largely  to  loss  of  vascular  spasm,  but  the  lowered 
general  combustion  rate  and  lessened  load  on  the  circulatory  system  also 
may  play  a  considerable  part. 

Recent  studies  on  the  production  of  malignant  hypertension  and  ar- 
teriosclerosis in  experimental  animals  has  suggested  the  possibility  that 
vascular  spasm  in  the  renal  vessels  of  man  may  be  an  important  factor  in 
the  sclerosis  picture.  It  may  be  for  this  reason  that  vascular  sclerosis  and 
failure  become  such  dominant  health  threats  in  the  most  energizing  and 
stressful  climates,  and  that  such  welcome  relief  is  brought  by  even  the 
brief  periods  of  summer  heat.  Fig.  15  on  a  preceding  page  indicated 
the   marked   lowering   in   the   incidence   of   heart   failure   during   summer 

Vol.  I.  941 


500(6)  CLIMATE   IN   HEALTH   AND    DISEASE 

warmth,  and  mention  also  was  made  of  the  similar  reduction  during  cer- 
tain Cincinnati  winters  when  balmy  weather  largely  prevailed.  It  does 
seem,  therefore,  that  climatic  and  seasonal  temperature  levels  constitute 
a  basically  important  factor  in  determining  vascular  stress  and  likelihood 
q{  functional  breakdown,  and  that  this  fact  should  receive  serious  con- 
sideration in  the  handling  of  patients  with  a  tendency  to  such  vascular 
troubles. 

In  this  matter  of  cool  climate  or  winter  stress  man  is  doubly  handi- 
capped. He  not  only  feels  the  urge  to  be  more  active  in  cool  weather, 
but  each  bit  of  work  he  does  then  costs  him  a  greater  expenditure  of 
energy  than  would  similar  work  accomplishment  in  summer  warmth. 
It  has  been  shown^®  that  body  working  efficiency  declines  as  tissue 
combustion  rate  rises,  so  that  the  climbing  of  a  given  flight  of  stairs 
carries  a  higher  metabolic  cost  in  winter  cold  than  it  does  in  summer 
warmth.  Man  in  cool  climates  thus  is  faced  both  with  the  urge  to  be 
more  active  and  to  pay  a  higher  metabolic  price  for  such  activity  than 
does  the  resident  of  warmer  regions.  It  may  well  be  this  combination  of 
stresses  that  is  at  the  basis  of  his  circulatory  failure  problem  in  middle 
temperate  regions. 

At  any  rate  it  would  seem  clearly  indicated  that  any  individual  show- 
ing evidences  of  the  effects  of  such  stress  should  be  advised  of  these 
factors  acting  upon  him  and  of  the  possible  benefits  of  migration  to  a  less 
energizing  climate,  and,  since  respiratory  infections  constitute  a  major 
threat  to  patients  with  limited  myocardial  capacity,  these  patients  should 
seek  particularly  for  freedom  from  winter  storminess  as  well  as  for  sooth- 
ing warmth.  Within  the  United  States  that  would  mean  southern 
Florida  or  the  Brownsville  region  of  Texas  rather  than  the  non-stormy 
but  slightly  more  stimulating  Southwest.  Advice  regarding  climatic 
therapy  for  these  patients  would  be  the  same  as  that  discussed  on  a  pre- 
ceding page  for  diabetics,  either  in  America  or  in  foreign  countries,  and  the 
same  precautions  should  be  observed  about  returning  to  cool,  stormy 
latitudes  except  during  the  milder  summer  months.  Many  people  with 
limited  cardiac  capacity  have  died  of  pneumonia  contracted  from  too 
early  a  spring  return  to  a  northern  home.  This  danger  will  be  discussed 
more  fully  under  respiratory  disease  considerations. 

Nervous  Disturbances 

For  mental  and  nervous  breakdown,  neuresthenia  and  related  exhaustion 
states  there  exist  less  clear  indications  for  advice  regarding  climatic 
therapy.     The  gray  matter  of  the  brain  has  the  highest  combustion  rate 

Vol.  I.  941 


CLIMATIC   THERAPY  500(7) 

of  all  body  tissues  and  should  be  expected  to  show  most  marked  evi- 
dences of  stress  in  populations  living  under  the  most  stimulating  climatic 
conditions.  Such  is  indeed  actually  the  case,  but  evidence  has  not  yet 
accumulated  to  show  whether  such  patients  would  be  as  much  benefited 
by  migration  to  more  soothing  climates  as  are  the  patients  with  metabolic 
and  hypertensive  troubles.  Cerebral  activity  does  seem  to  decline  with 
prolonged  external  warmth,  for  psychological  testing  of  college  freshmen 
in  lower  temperate  latitudes  gives  markedly  lower  ratings  during  summer 
heat  than  in  winter  cold,  while  at  higher  latitudes  the  milder  summer 
warmth  is  without  any  such  depressing  effect  on  mental  function.  It 
would,  therefore,  seem  desirable  to  try  climatic  sedation  in  cases  of  central 
nervous  exhaustion,  followed  by  the  mild  stimulation  of  such  non-stormy 
regions  as  northern  New  Mexico  or  Arizona  at  altitudes  of  5,000  to  6,000 
feet.  Any  such  climatic  therapy  should,  of  course,  be  accompanied  by 
very  restricted  use  of  tobacco  or  alcohol  and  complete  abstinence  from 
all  stimulants  of  the  caffeine  type.  It  seems  advisable  also  to  recommend 
a  high  intake  of  the  B  vitamins,  particularly  thiamine,  during  any  such 
effort  at  restoration  of  proper  cerebral  function. 

Infectious  Diseases 

So  far  as  is  known,  climatic  or  weather  conditions  have  little  to  do 
with  the  acute  contagious  diseases  of  childhood  except  as  the  indoor 
existence  of  the  winter  season  brings  greater  crowding  and  better  chance 
for  contagion  to  spread.  However,  for  respiratory  and  rheumatic  in- 
fections climatic  environment  seems  to  be  a  factor  of  really  dominant  im- 
portance. Sudden  stormy  changes,  particularly  those  accompanied  by 
sharp  temperature  drops,  initiate  the  infectious  attacks,  while  the  mean 
temperature  levels  under  which  people  live  largely  determine  ability  of  the 
body  to  fight  the  infectious  invasion.  Thus,  rheumatic  and  respiratory 
infections  occur  most  frequently  in  those  stormy  middle  temperate  re- 
gions where  body  resistance  is  highest.  This  is  indeed  fortunate,  for  a 
North  Dakota  winter  would  produce  a  holocaust  of  pneumonia  deaths  if 
suddenly  visited  upon  a  tropical  population. 

For  sinusitis,  bronchitis,  bronchiectasis  and  a  tendency  to  repeated 
''colds''  climatic  therapy  offers  very  definite  benefits.  This  is  again 
fortunate,  since  only  too  often  these  conditions  receive  little  benefit  from 
treatment  in  the  home  climate.  Epidemics  of  "colds"  and  other  respira- 
tory infections  continue  unabated  in  populations  during  stormy,  middle 
temperate  winters,  little  affected  by  all  the  claims  of  benefit  from  vaccine 
therapy,  vitamin  administration  or  general  nutritional  betterment.     For 

Vol.  I.  941 


5oo(8)  CLIMATE   IN    HEALTH   AND    DISEASE 

most  individuals  susceptible  to  recurrent  attacks  of  these  respiratory 
troubles  migration  to  a  non-stormy  region  offers  the  only  real  hope  of 
relief.  An  occasional  patient  with  chronic  bronchitis  will  be  cured  by 
attention  to  other  foci  of  infection  higher  up,  and  a  few  bronchiectatic 
patients  are  helped  by  lobectomy.  Therapy  for  acute  sinusitis  is,  in  the 
main,  beneficial,  but  after  the  sinus  changes  have  become  chronic,  the 
patient  can  look  forward  to  more  or  less  permanency  of  his  trouble  so 
long  as  he  continues  on  in  a  region  afflicted  with  frequent  waves  of  acute 
upper  respiratory  infections.  As  the  years  pass,  he  may  expect  a  spread- 
ing of  the  chronic  changes  to  other  nasal  accessory  cavities  and  to  the  bron- 
chial tree. 

An  important  element  in  this  steady  progression  of  involvement  is  the 
frequent  repetition  of  acute  flare-up  with  each  new  respiratory  epidemic 
that  comes  along  or  with  each  body  chilling  that  takes  place.  Persons 
with  these  chronic  infections  are  unduly  sensitive  to  chilling  and  usually 
make  life  uncomfortable  for  those  with  whom  they  must  live.  High  in- 
door temperatures  and  freedom  from  drafts  must  be  maintained  for  their 
comfort.  Nor  is  this  sensitivity  to  chilling  at  all  psychic  on  their  part. 
Degrees  of  chilling  that  do  not  bother  normal  persons  in  the  least  may 
result  in  prompt  exacerbation  of  their  troubles.  For  such  afflicted  indi- 
viduals to  continue  living  through  northern  winters  usually  means  much 
trouble  for  themselves. and  discomfort  or  damage  to  others,  who  must 
inhabit  with  them  the  over-heated  living  quarters  and  face  the  sharp  con- 
trasts between  indoor  and  outdoor  air  as  they  come  and  go. 

Since  medical  science  as  yet  has  no  other  therapeutic  answer,  migra- 
tion out  of  cold  and  storms  should  be  seriously  considered  for  such  cases. 
If  they  cannot  migrate,  then  steps  should  be  taken  to  protect  them  from 
chilling  without  endangering  the  welfare  of  others  in  the  household  by 
over-heating.  Warmer  clothing,  particularly  for  the  extremities,  should 
be  the  basis  of  any  needed  additional  protection  for  the  affected  indi- 
vidual. * 

Great  benefit  v/ill  come  to  the  chronically  afflicted  respiratory  disease 
patient  from  winter  migration  out  of  northern  cold  and  storms  or  from 
permanent  change  of  residence  to  the  plateau  regions  of  the  Southwest. 
Wintering  in  Florida  or  in  the  warmth  along  the  Gulf  Coast  offers  less  re- 
lief because  of  two  storm  factors.  As  shown  in  Fig.  21,  cold  waves 
travel  well  southward  down  the  Plains  States  during  the  winter  months, 
giving  the  Southern  States  then  almost  as  great  an  atmospheric  turbulence 
as  is  encountered  in  the  North.  In  addition,  tropical  low-pressure  storms 
sweeping  westward  over  the  West  Indies  and  Caribbean  region  bring 
added  instability  during  the  earlier  winter  months.     These  latter  storms 

Vol.  I.  941 


CLIMATIC   THERAPY  500(9) 

cause  little  temperature  change,  but  their  sharp  pressure  fluctuations 
seem  to  bring  on  many  of  the  same  body  disturbances  that  are  associated 
with  temperate  zone  storm  changes.  Respiratory  infections  and  deaths 
increase  just  as  much  from  summer  low  to  winter  high  in  Georgia  as  they 
do  in  New  York.  Only  well  south  in  Florida  or  in  the  Brownsville  district 
of  Texas  is  there  relative  freedom  from  the  northern  type  of  winter  storm, 
but  even  these  regions  remain  afflicted  with  those  of  tropical  origin. 

Winter  migration  for  relief  from  respiratory  troubles  should,  therefore, 
be  directed  toward  the  southwest  rather  than  to  the  south.  Moderate 
elevations  within  200  miles  of  the  Mexican  border  from  El  Paso  west  will 
be  found  to  offer  most  nearly  ideal  weather  conditions  for  this  purpose. 
Locations  for  permanent  residence  might  be  selected  slightly  farther  north 
on  account  of  summer  heat  but  probably  not  far  beyond  the  northern 
borders  of  New  Mexico  or  Arizona.  The  point  should  be  stressed  that 
migration  benefits  soon  disappear,  if  the  patient  returns  to  northern  cold 
and  storms,  even  though  complete  subsidence  of  trouble  may  have  pre- 
vailed for  a  considerable  period  in  the  non-stormy  climate.  For  those 
persons,  severely  handicapped  by  recurring  respiratory  troubles,  per- 
manent change  of  climate  is,  therefore,  strongly  advised,  since  it  offers 
hope  for  a  more  normal  existence  of  health  and  usefulness. 

Tuberculosis.  - —  This  disease  deserves  consideration  from  at  least  two  cli- 
matic angles,  even  though  one  today  so  often  hears  specialists  in  this  field  de- 
clare that  change  of  climate  offers  these  patients  nothing  that  cannot  be  had 
without  leaving  the  home  region.  The  same  two  principles  of  climatic  effect 
work  in  tuberculosis  as  in  other  chronic  or  semi-chronic  respiratory  infec- 
tions, and  failure  to  recognize  their  value  only  mitigates  against  the  pa- 
tient's chance  for  recovery.  Acute  intercurrent  respiratory  infections  carry 
serious  dangers  for  people  with  subacute  or  active  tuberculosis  because  of 
their  tendency  to  light  up  the  tuberculosis  process,  and  these  acute  in- 
fections come  largely  with  sudden  storm  changes  in  weather.  Hence,  on 
this  point,  the  tuberculosis  patient  reduces  his  disease  hazards  greatly  by 
migration  to  a  non-stormy  climate.  He  may  receive  the  same  effective 
nutritional,  rest  and  collapse  therapy  in  all  regions,  where  proper  facilities 
are  available,  but  only  in  a  non-stormy  climate  may  he  achieve  freedom 
from  recurring  acute  infections. 

The  second  point  deserving  emphasis  in  tuberculosis  relates  to  those 
patients  contracting  the  disease  in  regions  of  debilitating  moist  heat  or  to 
those  with  quiescent  forms  of  the  disease  who  contemplate  any  prolonged 
sojourn  in  tropical  warmth.  The  marked  lowering  of  tissue  resistance  to 
infection  in  tropical  moist  heat  makes  it  imperative  that  patients  develop- 
ing the  disease  there  be  transferred  at  once  to  a  more  stimulating  climate 

Vol.  I.  941 


50o(io)  CLIMATE   IN   HEALTH   AND    DISEASE 

where  a  higher  tissue  combustion  rate  can  be  maintained.  The  most 
perfect  diet  cannot  secure  nutritional  betterment  in  such  patients  so  long 
as  difficulty  in  body  heat  loss  interferes  with  its  utilization  by  the  tissues. 
Transfer  of  these  patients  from  debilitating  tropical  heat,  however,  should 
never  be  to  a  region  afflicted  with  storms  but  rather  to  a  such  non- 
stormy,  mildly  stimulating  climate  as  is  offered  at  moderate  elevations  in 
our  Southwest.  Patients  even  with  completely  quiescent  tuberculosis 
should  be  advised  against  any  prolonged  sojourn  in  tropical  heat,  since 
the  sharp  lowering  of  tissue  vitality  may  bring  on  a  re-lighting  of  the 
infection. 

The  dangers  of  migration  into  stormy  temperate  regions  after  any 
prolonged  stay  in  tropical  or  subtropical  warmth  should  be  kept  in  mind 
always.  For  a  northerner  to  make  a  winter  visit  of  a  week  or  two  in  the 
warmth  of  southern  Florida  entails  no  health  risk,  but,  if  he  remains  there 
for  several  weeks,  his  lowered  combustion  rate  renders  him  liable  to  seri- 
ous respiratory  infection,  if  he  return  northward  while  winter  weather 
still  prevails.  This  applies  particularly  to  the  elderly  winter  migrant  to 
southern  warmth.  Return  to  northern  homes  should  be  delayed  until  all 
danger  of  winter  cold  and  storms  is  past.  Movement  of  tropical  residents 
to  temperate  regions,  particularly  those  patients  run  down  by  debilitating 
disease,  should  be  carried  out  during  summer  warmth  and  with  careful 
protection  against  weather  changes  during  the  entire  first  winter. 

Rheumatic  Infections.  —  Rheumatic  infections  seem  very  closely  similar 
to  those  of  the  respiratory  system  in  their  relationship  to  storminess  and 
weather  change.  This  similarity  may  well  be  more  than  coincidental,  for 
several  investigators  have  felt  that  rheumatic  infections  are  probably 
secondary  to  those  of  the  respiratory  system.  Considerable  ground  for 
this  belief  is  provided  by  the  great  frequency  with  which  acute  rheumatic 
fever  attacks  accompany  or  follow  those  of  the  upper  respiratory  pas- 
sages. Whether  this  relationship  be  real  or  only  seemingly  apparent,  the 
strong  tendency  of  rheumatic  attacks  to  flare  up  in  stormy  seasons  makes 
it  imperative  that  these  patients  be  protected  as  far  as  possible  from 
weather  changes.  Unfortunately  they  seem  most  sensitive  to  barometric 
pressure  fluctuations,  against  which  modern  housing  provides  no  protec- 
tion. Body  chilling,  to  which  they  are  also  sensitive,  is  as  bad  for  them  as 
it  is  for  patients  with  chronic  upper  respiratory  infections. 

The  hazards  of  an  active  existence  in  stormy  regions,  especially  during 
winter  cold,  are,  therefore,  even  greater  for  patients  with  rheumatic  in- 
fections than  for  those  with  respiratory  troubles.  Involvement  of  the 
heart  with  limitation  of  cardiac  functional  capacity  by  valvular  lesions 
further  complicates  their  winter  problem.    This  phase  of  the  problem  was 

Vol.  I.  941 


CLIMATIC   THERAPY  500(11) 

discussed  in  connection  with  sclerotic  heart  failure.  The  indications  for 
migration  of  rheumatic  patients  to  a  non-stormy  climate  are,  therefore, 
quite  evident  and  emphatic.  As  with  the  respiratory  infections  migration 
should  be  to  the  Southwest  rather  than  the  South.  Transportation  of 
rheumatic  patients  to  Florida  or  Puerto  Rico  has  brought  rather  dis- 
appointing results,  while  in  southern  Arizona  and  New  Mexico  much 
more  complete  quiescence  of  the  disease  has  been  obtained.  The  reason 
for  the  better  results  in  the  southwest  probably  lies  in  the  year-round  lack 
of  storms  there  as  contrasted  to  a  winter  storminess  from  Texas  eastward 
almost  as  great  as  afflicts  the  northern  states. 

Migration  for  patients  with  rheumatic  infections  should  be  permanent, 
if  possible,  since  recrudescence  is  likely  to  follow  return  to  northern  cold 
and  storms.  If  only  winter  migration  is  possible,  then  that  should  even 
more  certainly  be  to  the  Southwest,  since  little  storm  relief  will  be  ex- 
perienced in  the  Gulf  States  at  that  season.  For  every  patient  developing 
definite  rheumatic  infection  migration  to  a  less  stormy  climate  should  be 
considered.  This  is  particularly  true  with  the  young  in  whom  heart 
lesions  are  so  likely  to  develop  as  the  infection  continues  through  the 
months. 

Regions  of  choice  for  migration  of  rheumatic  patients  should  be  to 
within  200  miles  of  the  Mexican  border  anywhere  west  of  El  Paso.  Acute 
rheumatic  fever  attacks  and  deaths  are  relatively  high  in  frequency 
throughout  the  mountain  and  plateau  states  even  as  far  south  as  the  north- 
ern parts  of  New  Mexico  and  Arizona^^.  Return  visits  of  migrants  to  former 
home  regions  should  be  made  during  summer  months  when  storm  tur- 
bulence is  at  a  minimum. 

Leprosy.  —  Leprosy  is  another  infectious  disease  markedly  influenced  by 
climatic  differences  in  resistance  to  infection-^.  It  exists  as  a  terrible  hu- 
man scourge  only  in  those  tropical  lowlands  shown  in  Fig.  10  as  having  the 
lowest  order  of  climatic  stimulation.  In  more  stimulating  regions  it  ceases 
to  be  an  active  disease  and  becomes  practically  non-communicable.  In 
tropical,  moist  heat  it  spreads  easily  and  involves  considerable  percentages 
of  population  masses  in  some  areas,  while  there  was  practically  no  spread 
from  200  cases  imported  into  the  stimulating  Minnesota-Dakota  region 
during  the  19th  century  migration  from  Scandinavia.  Only  during  the 
world  warmth  of  the  Dark  Age  centuries  did  leprosy  become  really  active 
in  temperate  zone  countries.  In  view  of  the  disease  behavior  over  the 
earth,  it  would  seem  wise  to  segregate  patients  afflicted  with  the  disease 
in  climatic  regions  where  their  own  ability  to  fight  the  infection  will  be 
highest  rather  than  to  follow  the  custom  now  prevailing  of  segregation 
where  the  disease  itself  is  worst.     In  America  that  would  mean  moving 

Vol.  I.  941 


500  (i2)  CLIMATE    IN   HEALTH   AND    DISEASE 

the  National  Leprosarium  from  Louisiana  to  North  Dakota.  In  any  such 
move  great  care  would  need  to  be  exercised  during  the  first  winter  to  pro- 
tect the  patients  against  the  unaccustomed  vigors  of  northern  winter,  for 
they  would  be  highly  susceptible  to  respiratory  infections  until  they  had 
resided  for  some  time  in  the  more  invigorating  climate.  This  principle 
already  is  being  put  into  practice  to  some  degree  in  Australia,  but  the  idea 
seems  worthy  of  much  more  widespread  application.  Altitude  stimulation 
in  tropical  highlands  is  never  far  removed  from  the  lowland  areas  of  de- 
bilitating moist  heat. 

Air  Conditioning 

It  cannot  yet  be  said  just  how  far  man  will  be  able  to  go  in  overcom- 
ing natural  climatic  or  weather  effects  by  interior  conditioning  methods. 
It  has  been  shown  quite  clearly  that  the  biological  let-down  of  summer 
warmth  can  be  eliminated  by  adequate  artificial  cooling  to  facilitate  body 
heat  loss.  Productivity  and  physical  vigor  of  tropical  workers  increases 
in  proportion  as  the  temperature  of  their  working  environment  is  lowered, 
but  if  such  summer  cooling  is  done  by  cooling  and  dehumidification  of  the 
indoor  air,  then  the  sharp  contrast  faced  by  people  entering  and  leaving 
such  conditioned  quarters  tends  to  raise  somewhat  the  same  problems 
that  are  brought  by  the  outdoor  unstable  weather  conditions  of  winter 
storminess. 

Indoor  winter  heating,  if  accomplished  through  air  warming,  also  pro- 
vides sharp  contrast  between  indoor  and  outdoor  air  and  so  increases 
whatever  health  dangers  reside  in  sudden  atmospheric  changes.  Ameri- 
cans wuth  their  careful  maintenance  of  stable  indoor  temperatures  far 
above  outside  levels  seem  only  to  have  accentuated  their  respiratory  dis- 
ease problems.  Perhaps  the  British  custom  of  lower  indoor  winter  tem- 
peratures is  after  all  better  than  what  they  have  termed  our  over-heating. 

If  proper  control  of  body  heat  loss  to  prevent  winter  chilling  or  sum- 
mer depression  is  to  be  accomplished  without  producing  contrasts  between 
indoor  and  outdoor  air,  then  it  will  have  to  be  done  through  radiant 
channels.  Very  recent  studies-^  have  shown  that  radiant  conditioning  is 
indeed  feasible  both  for  winter  heating  and  summer  cooling.  Certain 
difficulties  remain  to  be  overcome,  but  the  great  advantages  of  this  type 
of  conditioning  almost  certainly  will  bring  it  quickly  to  the  fore.  If 
heat-reflective  wall  coverings  be  used,  then  individuals  in  a  room  can  be 
made  comfortable  in  either  winter  cold  or  summer  heat  through  radiant 
channels  alone  without  regard  to  air  temperatures  or  humidity.  Radiant 
heating  in  the  winter  is  easily  accomplished.     Adequate  removal  of  body 

Vol.  I.  941 


BIBLIOGRAPHY  500  (13) 

heat  through  radiant  channels  for  summer  cooHng  is  more  difficult  but 
has  operated  satisfactorily  under  both  experimental  and  field  conditions. 

Present  air  conditioning  has  brought  remarkable  therapeutic  benefits 
to  one  class  of  human  sufferers,  the  sensitization  or  asthma  patients.  To 
many  complete  relief  has  come  by  thorough  filtering  and  condition  of  their 
indoor  atmosphere,  but  this  relief  does  not  extend  beyond  the  conditioned 
space. 

Air  conditioning  engineers  can  readily  bring  tropical  climates  to  tem- 
perate cities  or  provide  temperate  coolness  in  tropical  regions.  It  remains 
for  the  future  to  show  just  what  therapeutic  use  may  be  made  of  such 
facilities.  The  use  of  artificial  moist  heat  for  northern  toxic  goiter  pa- 
tients was  suggested  on  an  earlier  page  and  seems  well  worth  trying. 
Similar  artificial  depression  of  metabolism  might  be  tried  in  other  over- 
dynamic  states,  both  physical  and  mental.  Summer  cooling  is  strongly 
indicated  for  the  ill  during  severe  heat  waves,  while  in  the  tropics  re- 
cuperation can  be  greatly  hastened  by  properly  facilitating  body  heat 
loss. 

It  is  to  be  hoped  that  the  reader  will  see,  after  careful  perusal  of  this 
chapter,  that  the  therapeutic  duties  of  a  physician  can  no  longer  be  con- 
cerned simply  with  the  specific  treatment  of  the  disease  at  hand.  He 
should  look  farther  afield  for  the  larger  forces  affecting  his  patient's  wel- 
fare and  future  health.  And  among  the  outside  forces  bearing  on  these 
more  general  aspects  of  existence,  climatic  and  weather  influences  are  of 
great  importance.  The  most  perfect  diet  cannot  lead  to  physical  vigor 
and  high  vitality  unless  the  heat  generated  in  its  use  can  be  readily  dissi- 
pated from  the  body.  The  physician  of  the  future  will,  therefore,  need  to 
develop  more  deeply  his  interest  in,  and  knowledge  of,  climatic  and  me- 
teorologic  influences  affecting  man  throughout  his  existence  in  the  different 
regions  of  the  earth. 

BIBLIOGRAPHY 

1.  BENEDICT,  F.  G.  and  CATHCART,  E.  P.:    Muscular  work:    a  metabolic 

study  with  special  reference  to  the  efficiency  of  the  human  body  as  a  ma- 
chine, Carnegie  Institution  of  Washington,  Pub.  #187,  1913. 

2.  BRODY,  S.  and  TROWBRIDGE,  E.  A.:   Efficiency  of  horses,  men  and  motors, 

Univ.  of  Missouri  Agricultural  Exper.  Station  Bull.,  #383,  1937. 

3.  ZUNTZ,  N.:    Uber  den  Stoffverbrauch  des  Hundes  bei  Muskelarbeit,  Pfliiger's 

Arch.  f.  d.  ges.  Physiol.,  1901,  LXXXIII,  191. 

4.  BENEDICT,  F.  G.  and  CARPENTER,  T.  M.:    "Food  ingestion  and  energy 

transformation,  Carnegie  Inst,  of  Washington,  Pub.  #261,  1918. 
Vol.  I.  941 


50o(i4)  CLIMATE    IN    HEALTH    AND    DISEASE 

5.  MILLS,  C.  A.:   Climate  and  metabolic  stress,  Am.  Jour.  Hygiene,  1939,  XXIX, 

147. 

6.  GESSLER,  H.:   Untersuchungen  iiber  die  Warmeregulation.     I.    Mitteilung  die 

Konstanz  des  Grundumsatzes,   Pfluger's  Arch.   f.   d.   ges.    Physiol.,    1925, 

CCVII,  370. 

7.  MARTIN,  C.  J.:   Thermal  adjustments  of  man  and  animals  to  external  condi- 

tions. Lancet,  1930,  II,  617. 

8.  MILLS,   C.  A.:    Geographic  and  time  variations  in  body  growth  and  age  at 

menarche.  Human  Biology,  1937.  IX,  43. 

9.  MILLS,  C.  A.  and  SENIOR,  F.  A.:    Does  climate  affect  the  human  conception 

rate?    Arch.  Int.  Med.,  1930,  XLVI,  921. 

10.  MILLS,  C.  A.  and  OGLE,   C.:    Physiologic  sterility  of  adolescence.   Human 

Biology,  1936,  VIII,  607. 

11.  MILLS,  C.  A.:   Susceptibility  to  tuberculosis:   race  or  energy  level?    Am.  Jour. 

Med.  Sci.,  1935,  CLXXXIX,  330. 

12.  MILLS,  C.  A.:    Acute  appendicitis  and  the  weather,  Jour.  Med.,  Cincinnati, 

1934,  XV,  39- 

13.  LOCKE,  ARTHUR:    Lack  of  fitness  as  the  predisposing  factor  in  infections  of 

the  type  encountered  in  pneumonia  and  in  common  cold.  Jour.  Infect.  Dis., 
1937,  LX,  106. 

14.  COWGILL,  G.  R.:    Vitamin  B  Requirement  of  Man,  Yale  Univ.  Press,  New 

Haven,  1934. 

15.  MILLS,  C.  A.:    Unpublished  findings. 

16.  MILLS,  C.  A.:    Medical  Climatology,  Chas.  C.  Thomas,  Springfield,  1939. 

17.  JOSLIN,  E.   P.:    The  universality  of  diabetes.  Jour.  Am.  Med.  Assoc,   1940, 

CXV,  2033. 

18.  BEAN,  W.  B.  and  MILLS,  C.  A.:    Coronary  occlusion,  heart  failure  and  en- 

vironmental temperatures,  Am.  Heart  Jour.,  1938,  XVI,  701. 

19.  MILLS,  C.  A.:    Dangers  to  Southerners  in   northward   migration.   Am.   Jour. 

Trop.  Med.,  1935,  XV,  59i- 

20.  MOUNTIN,  J.  W.  and  HAROLD,  F.  D.:    Some  peculiarities  in  the  geography 

of  cancer.  Jour.  Am.  Med.  Assoc,  1939,  CXIII,  2405. 

21.  MILLS,  C.  A.  and  OGLE,  C:    Climatic  basis  for  susceptibility  to  heat  stroke 

or  exhaustion.  Am.  Jour.  Hygiene,  1933,  XVII,  686. 

22.  DAFT,  F.  S.,  SEBRELL,  W.  H.,  BABCOCK,  S.  H.  and  JUKES,  T  H.:   Ef- 

fect of  synthetic  pantothenic  acid  on  adrenal   hemorrhage,  atrophy,  and 
necrosis  in  rats.  Pub.  Health  Rep.,  1940,  LV,  1333. 

23.  MILLS,  R.  C,  SHAW,  J.  H.,   ELVEHJEM,  C.  A.  and  PHILLIPS,  P.  H.: 

Curative  effect  of  pantothenic  acid  in  adrenal  necrosis,  Proc  Soc  Exper. 
Biol,  and  Med.,  1940,  XLV,  4824. 

24.  MILLS,  C.  A.:   Depressions,  weather  and  health.  Human  Biology,  1939,  X,  383. 

25.  HUNTINGTON,  ELLSWORTH:    Civilization  and  Climate,  Yale  Univ.  Press, 

New  Haven,  1925. 

26.  McCLINTOCK,  J.  T.  and  PAISLEY,  S.:    Cost  of  work  in  relation  to  basal 

metabolism,  Proc.  Soc.  Exper.  Biol,  and  Med.,  1932,  XXX,  162. 
Vol.  L  941 


BIBLIOGRAPHY  500  (15) 

27.  MILLS,  C.  A.:  Seasonal  and  regional  factors  in  acute  rheumatic  fever  and  rheu- 

matic heart  disease,  Jour.  Lab.  and  Clin.  Med.,  1938,  XXIV,  53. 

28.  MILLS,  C.  A.:    World  leprosy  in  relation  to  climatic  stimulation  and  bodily 

vigor,  Internal.  Jour.  Leprosy,  1936,  IV,  295. 

29.  MILLS,  C.  A.:    Control  of  body  heat  loss  through  radiant  means,  Journal  Sec- 

tion of  Heating,  Piping  and  Air  Conditioning,  1937,  IX,  697. 
Sept.  I,  1941. 


Vol.  L  941 


CHAPTER  XII 
HEREDITY  AND  EUGENICS  IN  RELATION  TO  MEDICINE 

By  CHARLES  B.  DAVENPORT 

Table  of  Contents 

General  Statement  about  Heredity Soi 

Nature  of  Heredity  and  Environment So3 

Sketch  of  Mechanism  of  Heredity 5o5 

General  Considerations S05 

Method  of  Inheritance  of  Particular  Traits So6 

Inheritance  of  Special  Traits,  particularly  Diseases  and  Defects  ....  510 

Introductory  Remarks 5^° 

Resistance  and  Longevity ^     •      •      •  5" 

The  Allergies  and  Vitamin  Insufficiencies 512 

Twin  Production 5i2 

The  Internal  Secretions  and  Constitution 513 

Abnormal  Growths S^S 

Skin  Diseases S^o 

Skeletal  System S16 

Muscular  System 5i7 

Nervous  System S^° 

Sense  Organs 5  20 

Alimentary  System 520  (i) 

Respiratory  System 52°  (i) 

Circulatory  System S20  (2) 

Summary 520  (2; 

Applied  Eugenics 520  (3) 

I.   GENERAL   STATEMENT  ABOUT  HEREDITY 

In  order  to  understand  the  relations  of  genetics,  or  the  science  of  heredity, 
to  medicine,  it  is  necessary  to  be  clear  on  the  biological  significance  of  heredity. 
If  two  fertilized  eggs,  one  of  a  starfish  and  one  of  a  sea  urchin,  are  placed  in  a 
finger  bowl  of  sea  water  under  otherwise  favorable  conditions  each  will  develop 
in  its  own  way;  one  into  a  young  starfish  and  the  other  into  a  young  sea 
urchin.  The  eggs  are  both  nearly  microscopic,  they  look  very  much  alike  even 
under  the  microscope.    The  conditions  surrounding  them  are  as  nearly  identical 

Vol.  I.  934 

SOI 


502     HEREDITY  AND   EUGENICS   IN   RELATION  TO  MEDICINE 

as  possible.  Yet  they  develop  into  very  different  organisms,  of  different  form 
and  different  activity.  This  difference  in  the  course  of  development  of  two 
fertilized  eggs,  surrounded  by  identical  environment,  can  only  be  due  to  a 
difference  in  internal  factors  which  control  their  development.  The  internal 
factors  which  control  the  development  of  the  organism  are  what  we  understand 
as  heredity. 

This  property  of  the  fertilized  egg  to  reproduce  the  specific  form  to  which 
it  belongs  is  universally  recognized.  A  child  of  two  Scandinavian  parents  has 
at  birth  a  trunk,  two  arms  and  two  legs,  a  practically  hairless  skin  and  facial 
features  of  such  and  such  form  because  it  develops  from  Scandinavian  proto- 
plasm. A  child  of  two  Negro  parents  has  a  different  colored  skin  and  a 
different  form  of  hair  and  different  features  because  it  develops  from  Negro  pro- 
toplasm. This  is  heredity.  Everybody  believes  in  heredity,  even  those  who  deny 
its  importance.  The  two  white  parents  who  would  be  appalled  at  having  a 
black-skinned  baby  believe  in  heredity.  The  person  who  invests  ten  cents  in  a 
package  of  seeds  marked  "double,  variegated  petunias"  has  a  deep  faith  in 
heredity.  The  only  limitation  to  universal  belief  in  heredity  is  in  respect  to  its 
application  to  particular  cases.  If  a  man  has  his  forefinger  cut  off  by  a  hay 
knife,  we  recognize  that  this  peculiarity  which  he  carries  through  his  later  life 
is  not  due  to  heredity.  If  a  man  is  born  with  four  fingers  and  belongs  to  a 
family  in  which  for  generations  numerous  persons  have  been  born  with  only 
four  fingers  instead  of  five,  the  special  student  of  genetics  will  emphatically 
pronounce  his  peculiarity  to  be  hereditary.  If,  however,  a  single  case  appears 
in  a  family  of  a  child  born  with  a  finger  which  has  been  constricted,  or  perhaps 
entirely  lost  off  before  birth,  we  are  in  more  doubt  as  to  whether  this  is  a  case 
of  uterine  accident,  constriction  of  the  developing  finger  by  adhesion  to  em- 
bryonic membranes,  or  whether  there  is  in  this  case  a  genetic  hereditary  factor. 
We  are  familiar,  also,  with  striking  instances  of  members  of  the  same  family 
who  have  not  been  in  close  contact  and  who,  nevertheless,  show  similar  ges- 
tures, idiosyncrasies  of  speech,  or  special  gifts.  Popularly  these  idiosyncrasies 
are  recognized  as  hereditary.  But  when  one  member  of  the  family  is  feeble- 
minded, or  has  epileptic  fits,  or  shows  a  lack  of  control  over  actions  such  as 
makes  it  necessary  to  remove  him  from  society,  then  a  great  difference  of 
opinion  arises  as  to  whether  these  conditions  are,  or  are  not,  hereditary. 

Heredity  is  not  to  be  regarded  as  a  phenomenon  of  the  same  order  as  a 
particular  disease  entity  or  syndrome.  It  is  something  more  fundamental 
and  universal  than  that.     It  is  the  internal  direction  of  development. 

The  developing  egg  of  a  particular  species,  if  surrounded  by  a  proper  en- 
vironment and  if  its  internally  directing  agents  are  typical  of  the  species  and 
are  without  lethal  factors,  will  develop  in  a  predictable  fashion  to  produce  the 
specific  form  with  its  particular  function.    The  egg  is  more  or  less  spherical  and 

Vol.  I.  934 


NATURE   OF   HEREDITY  AND   ENVIRONMENT  503 

contains  somewhat  unequally  distributed  particles  of  varied  molecular  constitu- 
tion. Always  in  its  center  is  the  egg  nucleus,  formed  by  the  union  of  the 
pronuclei  of  sperm  and  egg.  The  nucleus  contains,  floating  in  a  fluid,  a  proto- 
plasmic network  in  which  lie  granules.  Before  any  cell  division  takes  place  the 
granules  come  together  in  the  form  of  elongated  chromosomes.  In  the  act  of 
cell  division  each  of  the  chromosomes  divides  precisely  so  that  each  daughter 
cell  contains  the  same  chromosomes  as  the  mother  cell.  In  the  chromosomes 
are  the  specific  activators  of  development  (enzymes,  called  "genes"),  which 
control  time  and  place  of  cell  divisions  and  other  developmental  processes 
that  eventually  lead  to  the  adult  form. 

Nature  of  Heredity  and  Environment 

One  of  the  commonest  inquiries  made  of  the  geneticist  is  as  to  the  relative 
importance  of  heredity  and  environment.  This  seems  to  be  regarded  by  persons 
of  large  experience  and  vision  and  especially  by  those  interested  in  social 
improvement  as  a  fundamental  question.  It  is  frequently  thought  that  those 
interested  in  human  biology  and  sociology  fall  into  two  groups,  the  heriditarians 
and  the  environmentalists. 

Such  a  division  is  very  unfortunate  and  entirely  unwarranted.  There  is  in 
Nature  no  such  contrast.  Huxley  has  somewhere  described  life  as  the  inter- 
action between  the  internal  organism  and  external  world,  and  this  interaction 
extends  even  to  the  smallest  living  cell. 

The  development  of  the  organism  and  the  metabolism  of  each  cell  are,  it  is 
sometimes  said,  determined  by  genes.  Others  stress  the  importance  of  the 
cytoplasm.  The  truth  seems  to  be  that  the  genes  by  themselves  can  do  nothing, 
the  cytoplasm  by  itself  is  so  inert  as  to  be  inefTective.  The  genes  act  as  cat- 
alysts, as  enzymes,  which  accelerate  the  chemical  processes  going  on  in  the 
cytoplasm,  determine  the  specific  chemical  reaction  that  shall  occur  at  any 
moment  in  the  cytoplasm  and  thus  determine  the  quality  of  the  cell,  whether 
it  is  a  bone  cell,  or  a  muscle  cell,  or  a  nerve  ceU,  or  whatever  its  form  and 
function  may  be.  It  will  be  noted  that  there  are  certainly  hundreds,  probably 
thousands,  of  different  kinds  of  enzymes  in  the  gene  complex  of  the  cell,  that 
there  are  scores,  possibly  hundreds,  of  different  kinds  of  molecules  in  the  cyto- 
plasm, that  at  a  given  moment  only  a  particular  enzyme  can  accelerate  a 
particular  cytoplasmic  operation.  Therefore,  the  action  of  the  hereditary  units 
is  determined  absolutely  by  the  nature  of  the  cell  which  is  environmental  to 
them,  and  the  changes  that  take  place  in  the  cytoplasm  are  determined  abso- 
lutely by  the  available  enzymes. 

Similar  are  the  relations  between  the  organism  and  its  environment.  The 
organism  can   do   nothing   without  its  environment;    what   the   environment 

Vol.  I.  934 


504    HEREDITY  AND   EUGENICS   IN  RELATION  TO  MEDICINE 

does  to  the  organism  depends  upon  the  nature  of  the  organism.  Were  loo 
children  to  be  reared  from  birth  in  an  identical  environment,  being  brought  in 
contact  with  similar  cultural  conditions,  they  would  still  grow  up  to  be  very- 
different,  because  each  is  highly  selective  in  making  use  of  what  the  uniform 
environment  provides.  The  "best"  cultural  condition  for  one  may  be  the 
worst  for  another.  As  a  distinguished  Frenchman  once  said,  "The  equal  treat- 
ment of  unequals  is  the  greatest  inequality."  Though  unequals  may  be  brought 
in  contact  with  the  same  external  treatment,  what  use  they  make  of  that 
treatment  is  highly  selective  and  differential.  An  extreme  case  is  presented  by 
two  children  one  of  whom  is  color-blind  and  the  other  has  sharp  color  discrimi- 
nation. Looking  at  the  same  painting  or  the  same  autumn  foliage  the  two  wiU 
see  very  different  things.  Similarly,  if  in  a  school  room  one  child  is  deaf,  while 
another  has  excellent  hearing,  what  the  two  children  get  from  the  similar  oral 
instruction  of  the  teacher  may  well  be  very  dissimilar.  The  deaf  pupil  may, 
indeed,  secure  some  benefit  from  the  instruction,  but  does  it  in  a  very  different 
way  from  the  hearing  pupil.  Two  persons  may  find  the  taste  of  the  same 
substance  to  be  for  one  agreeable,  for  the  other  disagreeable. 

The  same  principles  apply  in  the  field  of  medicine.  During  an  epidemic  of 
influenza,  yellow  fever,  or  the  plague,  not  everybody  finds  the  dangerous 
destructive  agents  of  the  epidemic  to  be  such  for  him.  The  disease-inciting 
agent  is  destructive  for  those  organisms  which  are  not  prepared  to  resist  it. 

This  principle  is  illustrated  in  detail  in  the  case  of  leukemia  in  mice  as 
worked  out  by  Dr.  E.  C.  MacDowell  with  the  assistance  of  Potter,  Richter, 
Victor,  and  others.  In  a  colony  of  mice  which  had  been  inbred,  brother  and 
sister,  for  40  or  50  generations,  there  appeared  several  who  died  of  leukemia. 
A  study  of  their  pedigree  showed  they  were  all  derived  from  the  same  mother. 
If  from  a  mouse  about  to  die  of  leukemia,  blood  is  taken  and  inoculated  into 
another  mouse  of  the  same  strain,  but  which  has  not  reached  the  tumor  age, 
that  mouse  will  die  from  leukemia  within  a  week  or  ten  days.  The  demon- 
stration is  complete  that  inoculated  cells  carry  the  power  of  unrestricted  pro- 
liferation, and  this  we  think  of  as  the  "cause  of  death."  But  this  conclusion 
is  wrong;  for  if  a  part  of  the  same  inoculant  that  has  resulted  in  the  death  of 
one  mouse  be  put  into  an  unrelated  mouse  of  another  strain  then,  apart  from 
an  erythema  at  the  point  of  inoculation,  there  is  no  reaction,  and  the  mouse 
continues  its  life  unscathed.  One  sees  then  that  not  merely  the  malignant 
cells  are  the  cause  of  leukemia,  but  the  susceptibility  of  the  organism,  or  its 
inability  to  protect  itself  against  the  leukemic  cells.  We  are  prone  to  divide 
the  white  blood  cells  into  leukemic  cells  and  normal  cells.  It  is,  on  the  other 
hand,  quite  as  significant  to  divide  organisms  into  those  who  are  resistant  to 
rapidly  proliferating  leukemic  cells  and  those  who  are  non-resistant.  For  the 
non-resistant  organisms  the  environments  of  white  blood  cells,  which  are  leu- 

VOL.  I.  934 


SKETCH  OF  MECHANISM   OF  HEREDITY  505 

kemic  and  those  which  are  not,  are  fundamentally  different,  and  the  environ- 
ment of  the  leukemic  cell  is,  indeed,  a  fatal  one.  Again,  for  the  resistant 
mouse  the  leukemic  cells  are  no  longer  a  worse  environment  than  normal 
white  blood  cells.  Or,  looking  at  the  matter  the  other  way  around,  to  the 
leukemic  cells  a  non-resistant  mouse  is  a  good  environment,  while  the  resistant 
mouse  is  a  bad  environment;  but  for  the  normal  white  blood  cells  both  types 
of  mice  constitute  a  good  environment.  Thus,  we  see  that  no  environment  is 
absolutely  good  or  bad,  but  only  such  in  relation  to  the  particular  genetical 
strain  of  organism  with  which  it  reacts.  Also,  the  same  agency  may  be  geneti- 
cal from  one  standpoint  and  environmental  from  another  standpoint.  The  end 
result,  a  pathological  condition,  is  a  chemical  interaction  between  two  agents,  and 
there  is  no  reason  for  designating  one  as  the  hereditary  factor  rather  than  the  other. 
This  point  of  view  can  be  extended  for  the  whole  range  of  human  experience. 
In  the  field  of  crime  the  question  is  often  raised  whether  this  is  not  caused  by 
bad  environment.  This  inquiry  has  no  significance.  Precisely  the  same  en- 
vironment, which  is  bad  for  one  person  and  may  result  in  that  person  becom- 
ing a  criminal,  may  be  good  for  another  person  and  protect  him  from  becoming 
a  criminal.  Criminal  behavior  results  from  the  interaction  of  a  particular 
environmental  set-up  and  a  person  of  particular  constitution,  which  causes  in 
that  person  a  criminal  reaction.  On  the  contrary,  the  same  environmental 
set-up  might  cause  a  person  of  different  constitution  to  become  a  saint.  We 
should  speak  not  of  bad  environment  but  bad  interactions. 

Sketch  of  Mechanism  of  Heredity 

General  Considerations 

Analysis  of  a  chromosome  shows  that  it  is  made  up  of  a  strand  of  more  or 
less  spherical  bodies  called  chromomeres,  and  it  is  believed  that  at  the  center 
of  each  chromomere  there  lies  a  gene.  Indeed,  there  are  some  who  believe  that 
they  have  seen  the  gene.  Whether  this  is  true,  or  not,  the  genes  probably  are 
among  the  largest  organic  molecules  and  are  not  far  below  the  range  of  vision 
by  the  aid  of  the  ultra-violet  light  waves. 

The  genes  are  believed  to  be  enzyme  molecules  (ferments).  It  is  the  nature 
of  each  ferment  that  it  acts  only  upon  specific  molecules  to  accelerate  their 
chemical  interaction.  When,  at  any  moment,  there  is  no  pair  of  molecules 
present  whose  interaction  can  be  accelerated  by  a  particular  enzyme  that 
enzyme  does  not  function. 

Starting  out  with  a  full  equipment  of  enzymes  and  with  appropriate  equip- 
ment of  building  material  in  the  cytoplasm  of  the  egg,  the  catalytic  action  of 
enzymes  in  promoting  chemical  processes  begins,  and  since  in  the  act  of  cell- 

VOL.  I.   934 


5o6    HEREDITY  AND   EUGENICS   IN   RELATION  TO  MEDICINE 

division  the  different  materials  of  the  cytoplasm  are  sorted  out  in  different 
cells,  the  nature  of  the  interaction  varies  in  the  different  cells.  The  different 
forms  that  these  cells  assume  must  be  believed  to  be  due  to  a  difference  in  the 
materials  upon  which  the  appropriate  enzymes  work.  As  any  chemical  process 
is  completed,  whether  it  be  oxidation  or  dehydration  or  other,  there  is  estab- 
lished a  particular  new  molecular  set-up  upon  which  not  the  gene  responsible 
for  the  particular  change,  but  another  gene,  acts,  a  set-up  such  that  the 
molecules  responsible  for  the  original  particular  change  can  not  act.  Thus, 
the  essential  elements  of  appropriate  change,  at  proper  time  and  place,  are 
provided  for. 

From  this  point  of  view  the  form  of  man  and  of  the  twenty-six  trillion  cells 
which  constitute  a  man  are  determined  by  the  genes  and  cytoplasmic  materials 
stored  in  the  fertilized  egg.  If,  however,  the  genes  or  cytoplasmic  materials 
were  other  than  they  ordinarily  are,  then  there  would  be  produced,  an  organism 
perhaps,  but  not  a  man.  Man,  as  we  know  him,  is  the  visible  expression  of  the 
interaction  of  human  genes  and  human  cytoplasmic  materials.  Man  has  not 
determined  the  nature  of  these  substances,  but  the  nature  of  the  substances  has 
determined  man.  In  just  the  same  way  the  substance  in  any  fertilized  egg 
determines  its  specific  form,  a  pig,  a  snake,  a  jellyfish,  or  a  sponge.  From  this 
point  of  view  the  history  of  the  evolution  of  the  animal  kingdom  is  the  history 
of  the  changes  that  have  occurred  in  the  materials  of  the  germ  cells;  also,  the 
anatomical  and  histological  analysis  of  a  man  is  merely  a  study  of  the  visible 
end-result  of  the  inter-workings  of  the  substances  that  have  through  various 
spontaneous  or  mutative  processes  in  the  history  of  chromosomal  evolution 
come  to  lie  in  the  human  egg. 

Method  of  Inheritance  of  Particular  Traits 

If  two  individuals  having  precisely  the  same  germ  plasm  should  marry,  their 
offspring  would  be  exactly  alike  and  Uke  their  parents.  Ordinarily,  this  situa- 
tion is  not  realized,  since  the  germ  plasm  and  the  cytoplasm  of  the  eggs  that 
are  produced  in  the  same  parents  are  not  exactly  alike.  The  dissimilarity  of 
the  genes  is  due  to  the  fact  that  practically  all  human  matings  are  hybrid 
matings,  so  that  when  the  germ  cells  are  formed  in  the  body  some  of  them  are 
formed  with  genes  of  one  kind  and  others  with  dissimilar  genes.  It  is  probable 
that  the  cytoplasmic  particles  are  distributed  somewhat  differently  to  the 
different  eggs.  Consequently,  when  a  union  in  pairs  of  the  dissimilar  egg  cells 
and  sperm  cells  occurs,  the  offspring  differ  from  each  other  and  are  more  or  less 
unlike  their  parents.  If  one  of  the  parents  belongs  to  a  race  most  of  whose 
external  characters  are  very  dissimilar  to  those  of  the  race  to  which  the  mate 
belongs,  then  a  dilemma  appears  as  to  what  the  children  will  be  like.    Empiri- 

VoL.  I.  934 


SKETCH  OF  MECHANISM  OF  HEREDITY        507 

cally  we  find  that  if  the  father  is  short  in  stature,  has  curly  and  black  hair, 
deep  brown  eyes  and  swarthy  skin,  and  belongs  to  a  race  with  these  characters, 
while  the  mother  is  tall  and  blond  and  straight-haired,  blue-eyed  and  fair- 
skinned,  and  belongs  to  a  race  which  has  these  characteristics,  then  the  offspring 
will  be  in  these  respects  much  more  like  the  father  than  the  mother.  They  will 
be  short  and  have  curly  and  dark  brown  hair,  dark  eyes  and  swarthy  skin. 

The  phenomenon  of  reappearance  in  the  offspring  of  certain  of  the  traits  of 
the  father's  race  and  certain  of  the  traits  of  the  mother's  race  is  the  basis  of 
the  principle  of  dominance  which  plays  a  great  part  in  modern  genetics.  A 
racial  trait  is  said  to  be  dominant  when  it  appears  in  one  of  the  full-blooded 
parents  and  not  in  the  other  and  appears  in  all  of  the  offspring.  Dominance 
has  been  explained  in  different  ways.  According  to  one  theory,  the  gene  for  the 
trait  is  present  in  the  germ  cells  on  one  side  of  the  house  and  absent  in  the 
germ  cells  of  the  other  side  of  the  house,  but  in  the  offspring  it  is  present, 
though  in  a  diluted  condition.  The  trait  that  is,  on  this  theory,  absent  is 
called  "recessive."  The  offspring  of  the  cited  mating  do  not  show  the  recessive 
trait  though  they  carry  it  in  their  germ  cells.  If,  now,  two  persons  of  this 
origin  should  marry,  then  one  quarter  of  their  offspring  will  show  the  recessive 
trait,  three  quarters  will  show  the  dominant  trait  and  of  those  three  quarters, 
two  quarters  will  have  it  in  a  diluted  condition  again.  The  diluted  condition  is 
known  as  "heterozygosis"  and  the  individuals  of  mixed  origins  are  known 
as  "heterozygotic."  Those  offspring,  which  show  the  recessive  trait,  are 
"  homozygotic "  for  that  trait,  as  are  also  those  offspring  that  inherit  double 
dominance  of  any  trait. 

It  is  to  be  said  that  the  foregoing  theory  is  not  universally  accepted,  and 
there  are  many  cases  in  genetics  where  it  is  not  applicable.  The  gene  re- 
sponsible for  a  dominant  trait  may  be  opposed  by  a  gene  which  is  not  absent, 
but  is  modified  in  such  a  way  as  to  produce  the  recessive  trait.  The  two  op- 
posing genes  are  sometimes  spoken  of  as  "allelomorphs"  and  of  the  allelo- 
morphs one  is  dominant  and  the  other  is  recessive,  but  neither  is  entirely 
absent.  Heterozygous  dominants  differ  from  homozygous  dominants  in  this, 
that  the  eventual  trait  is  developed  in  less  complete  degree  than  in  homozygous 
dominants.  Thus  in  the  eye  color,  brown  pigment  is  dominant  over  the  absence 
of  brown  (blue  eye),  but  the  brown  pigment  is  deeper  in  the  homozygous 
dominant  than  in  the  heterozygous  dominant.  Similarly,  in  the  offspring  of  a 
Negro  and  a  European  the  dark  skin  pigmentation  is  dominant,  but  less  dark 
than  in  the  full-blooded  Negro.  It  is  believed  that,  where  there  are  two  doses 
of  a  gene  for  a  particular  trait,  the  two  doses  work  twice  as  fast  as,  and  more 
effectively,  in  creating  a  character  than  a  single  dose. 

A  second  principle  in  inheritance  is  that  different  traits  are  inherited  inde- 
pendently of  each  other.     Thus,  for  example,  if  one  parent  is  a  full-blooded 

Vol.  I.  934 


5o8    HEREDITY  AND   EUGENICS   IN   RELATION  TO   MEDICINE 

Negro  and  the  other  a  Scandinavian,  then  the  children  will  all  have  dark  eyes 
and  dark,  curly  hair  and  dark  skin  pigmentation.  If  two  such  children  marry, 
then  their  offspring  will  carry  the  opposing  traits  of  the  ancestral  races  in  di- 
verse combinations.  Thus,  one  may  have  a  dark  skin  pigmentation,  straight 
hair  and  narrow  nose,  another,  light  skin  pigmentation  with  woolly  hair  and 
broad  nose,  or  broad  nose  may  be  combined  with  straight  hair.  It  has  to  be 
recognized,  however,  that  the  old  idea  that  each  gene  produces  only  a  single 
effect  in  the  developing  organism  is  not  strictly  correct,  but  each  usually  has 
a  predominating  effect  and  various  minor  effects.  The  reason  for  this  is  found 
in  the  general  considerations  given  in  the  preceding  section,  where  it  is  pointed 
out  that  any  trait  that  is  developed  is  developed  because  of  the  interaction  of 
one  or  more  genes  responsible  for  this  development  and  the  cytoplasm  of  the 
egg  in  which  these  genes  have  come  to  lie,  and  it  is  clear  that  the  chemical 
interaction  rarely  will  be  limited  to  a  particular  and  single  chemical  reaction. 

What  determines  that  particular  traits  be  dominant  or  recessive  is  not 
definitely  explained  in  the  second  hypothesis  referred  to  above.  In  general, 
new  and  recent  mutations  result  in  bringing  about  a  recessive  trait  in  the 
offspring.  Most  of  the  developmental  defects  in  the  child  are  due  to  recessive 
factors.  Such  are,  for  example,  feeble-mindedness,  epilepsy,  melancholia  and 
many  others.  However,  not  all  deviations  from  the  normal  are  in  the  nature 
of  recessive  defects.  Many  of  the  abnormalities  in  the  development  of  the 
hand,  for  example,  are  of  the  dominant  type. 

The  dissimilar  nature  of  the  genes  in  the  germ  cells  of  the  father  and  the 
mother  are,  as  pointed  out,  responsible  for  the  dissimilarity  of  children.  How- 
ever, there  is  one  case  in  which  the  development  of  two  children  is  under  the 
influence  of  precisely  similar  genes.  This  is  the  case  of  identical  twins  in 
which,  it  is  commonly  believed,  two  embryos  arise  from  the  same  egg  at  an  early 
stage  of  its  development.  These  two  embryos,  therefore,  have  the  same  chro- 
mosomes and  constituent  genes  and  probably  very  similar  cytoplasm.  How- 
ever, it  is  to  be  noted  that  we  can  not  be  sure  that  the  cytoplasm  of  the  cells 
from  which  the  two  embryos  arise  is  identical,  and,  as  a  matter  of  fact,  it  not 
infrequently  happens  that  the  embryos  which  develop  with  a  single  chorion  are 
somewhat  diverse  in  form.  Such  diversity,  in  contrast  with  the  ordinary 
identity,  may  be  due  either  to  dissimilarity  of  the  cytoplasm  or  to  differences  in 
the  intrauterine  environment,  among  others  to  the  stealing  by  the  one  embryo 
of  an  undue  proportion  of  the  circulating  blood,  thus  depriving  the  other  twin 
of  its  proper  nourishment. 

The  genes  are  found  in  the  nuclei  of  the  germ  cells,  arranged  in  linear  series 
along  the  axes  of  the  chromosomes  of  the  nuclei.  In  man  there  are  twenty- 
four  pairs  of  these  chromosomes  of  which  one  member  of  each  pair  is  derived 
from  the  father's  germ  cell  and  one  from  the  mother's.    Of  the  twenty-four  pairs 

Vol.  I.  934 


SKETCH  OF  MECHANISM  OF  HEREDITY        509 

of  chromosomes,  however,  there  is  one  which  has  different  relations  in  the  two 
sexes.  Thus,  in  the  female  offspring  the  members  of  this  one  pair  are  identical 
in  their  chromosomal  content.  In  the  males,  on  the  other  hand,  the  members 
of  this  pair  have  dissimilar  chromosomal  content.  In  fact,  one  of  the  chro- 
mosomes contains  very  few  active  genes.  The  chromosome  which  is  inactive  is 
known  as  the  Y  chromosome,  whereas  the  active  chromosome  of  the  pair  is 
known  as  the  X  chromosome.  The  females  contain  two  X  chromosomes,  the 
male  only  one  X  chromosome  and  one  Y  chromosome.  This  difference  in 
number  of  the  X  chromosomes  determines  a  difference  between  the  two  sexes 
in  the  activity  of  the  genes  in  their  sex  chromosomes,  and  this  difference  of 
activity  is  responsible  for  the  fact  that  one  individual  develops  into  a  female 
and  the  other  into  a  male  with  differing  male  and  female  characteristics.  It  is 
true  that,  in  vertebrates,  many  of  the  differentiating  characters  of  male  and 
female  can  be  influenced  by  hormones  early  produced  by  the  gonads,  or  sex 
glands.  However,  the  quahty  of  the  gonads  is  determined  by  the  difference 
in  the  number  of  X  chromosomes.  In  the  eggs  of  insects  sex  is  determined  only 
by  the  number  of  X  chromosomes;  there  are  in  them  no  important  hormones 
secreted  by  the  gonads  which  influence  the  sexual  characteristics. 

One  consequence  of  the  existence  of  the  sex  chromosomes  is  a  difference  in 
inheritance  of  certain  traits  that  depend  upon  genes  which  lie  in  them.  Thus, 
a  recessive  gene  of  the  X  chromosome  in  a  male  zygote  will  show  itself  effective 
on  the  soma  that  develops  out  of  that  zygote,  whereas  a  similar  recessive  de- 
fect in  a  female  zygote  will  not  show  in  the  adult  body  because  the  recessive 
trait  will  be  covered  over  by  the  normal  dominant  trait.  There  are  a  number 
of  so-called  sex-linked  traits  known  in  man  which  appear  ordinarily  in  males, 
but  are  transferred  by  females  over  to  their  male  offspring.  Among  them 
are  color  blindness,  hemophilia,  and  optic  nerve  atrophv. 

There  are,  indeed,  certain  characters  in  man  which  seem  to  be  influenced 
not  directly  by  genes  but  indirectly  by  the  activity  of  the  gonads;  such  are 
known  as  sex-limited  characters.  Examples  are  the  beard  in  man  and  the 
large  spurs  and  comb  of  the  cock.  The  hen  does  not  lack  determiners  for 
large  spur  or  large  comb.  This  may  be  demonstrated  by  grafting  a  testis  into 
a  young  hen;  large  spurs  and  comb  and  male  coloration  soon  make  their 
appearance  under  the  stimulus  of  hormones  derived  from  the  male  gland. 

Heretofore  we  have  been  considering  characters  due  to  a  single  gene  whether 
dominant  or  recessive.  Many  traits  are  due  to  the  cooperation  of  two  or  more 
genes  which,  working  together,  are  responsible  for  a  single  trait.  For  example, 
the  dark  skin  pigmentation  of  Negroes  is  due  to  the  activity  of  two  pairs  of 
genes  which  probably  activate  the  oxidation  of  thyrosin  to  form  melanin.  If 
the  typical  number  is  reduced  through  hybridization  from  four  to  three,  two,  or 
one,  we  have  produced  the  various  diluted  types  of  pigmentation  known  as 

Vol.  I.  934 


5IO    HEREDITY    AND   EUGENICS   IN   RELATION  TO  MEDICINE 

sambo,  mulatto  and  quadroon.    Many,  if  not  most,  human  traits  are  due  to  the 
cooperation  of  two  or  more  pairs  of  genes. 

Thus  we  see  that  the  studies  of  the  last  two  or  three  decades  upon  heredity 
have  demonstrated  that  it  is,  at  the  same  time,  much  more  definite  and  much 
more  complex  than  had  been  anticipated.  Much  is  still  to  be  learned  about 
the  inheritance  of  traits  in  man.  The  near  future  will,  no  doubt,  show  that 
just  as  color  bhndness  and  sex  production  are  linked  in  the  sex  chromosomes 
so  other  traits  are  linked  in  others  of  the  two  dozen  pairs  of  chromosomes  in  the 
germ  cells  of  man.  The  determination  of  the  association  of  determiners  in  the 
twenty-four  chromosomes  is  one  of  the  alluring  fields  of  research  for  the  future. 

II.   INHERITANCE  OF   SPECIAL  TRAITS,*  PARTICULARLY 
DISEASES   AND   DEFECTS 

Introductory  Remarks 

The  deviations  from  normality  that  man  shows  fall  into  a  number  of 
categories.  Some  of  them  are  of  the  nature  of  developmental  defects,  others 
are  symptoms  of  disease  for  the  production  of  which,  in  some  cases,  a  parasitic 
organism  has  been  shown  to  be  one  factor.  Others  are  chemical  peculiarities 
of  the  body  due  to  defects  in  metabolism  and  abnormal  internal  secretions  of 
various  types.  Without,  however,  attempting  to  classify  the  different  causes 
of  the  abnormal  conditions  shown,  we  may  consider  them,  in  groups  according 
to  the  organs  chiefly  concerned. 

One  explanatory  remark,  however,  may  be  ventured.  Because  it  has  been 
demonstrated  that  there  is  a  particular  parasitic  microorganism  responsible  for 
the  particular  disease,"  it  does  not  follow  that  the  particular  symptoms  shown 
by  the  diseased  individual  are  solely  dependent  upon  that  microorganism  and 
its  activities.  In  a  great  epidemic,  like  that  of  influenza,  we  find  individuals  in 
the  same  house,  even  in  the  same  family,  who,  though  they  clearly  harbor  the 
germs  of  the  disease,  show  very  different  symptoms.  One  can  hardly  think  of 
the  parasitic  organisms  as  differing  in  virulence  in  such  cases;  rather  the  human 
beings  in  which  they  are  developing  differ  in  their  resistance  and  reactions  to 
the  germ.  Indeed,  as  every  farmer  knows,  the  harvest  of  his  planting  is  de- 
termined not  only  by  the  seed  put  into  the  soil,  but  also  by  the  qualities  of  the 
soil  itself.  Similarly,  the  symptoms  that  a  microorganism  will  induce  in  the 
body  depend  not  only  upon  the  particular  physiology  of  the  microorganism, 
but  also  upon  the  soil  in  which  it  grows,  namely,  the  chemical  constitution  of 
the  individual.     With  these  general  remarks  the  different  diseases  and  defects 

*  " BiblioRraphia  Eugcnica,"  published  as  a  supplement   to  the  "Eugenical  News,"  gives 
fairly  complete  references  to  writings  on  inheritance  of  special  traits. 
Vol.  I.  934 


RESISTANCE  AND   LONGEVITY  511 

found  in  man  may  be  considered  briefly  with  special  reference  to  the  part  that 
heredity  plays  in  inducing  or  modifying  them. 

Resistance  and  Longevity 

When  a  disease  or  a  death  occurs,  we  are  prone  to  assign  a  cause,  and  in  all 
well  organized  states  there  are  public  mortality  statistics  which  give  the  num- 
ber of  persons  dead  and  "the  cause  of  death."  The  "cause  of  death"  is  too 
narrowly  conceived.  A  person  does  not  die  merely  of  typhoid  fever,  but  dies 
of  an  inability  to  resist  the  development  of  the  typhoid  bacillus  in  his  body. 
Indeed,  the  mortality  statistics  instead  of  being  arranged  under  causes  of 
death  with  the  subdivision  typhoid  fever,  cancer,  etc.,  might  about  as  properly 
be  arranged  under  the  rubrics  "Number  of  persons  non-resistant  to  typhoid 
fever,"  "Number  of  persons  non-resistant  to  cancer,"  etc.  A  text  book  on 
bacteriology  describes  the  parasitic  organism  which  is  often  associated  with  the 
disease,  but  says  nothing  about  the  organism  in  which  the  disease-promoting 
germ  is  growing.  The  persons  who  die  of  a  particular  disease,  like  typhoid 
fever,  are,  however,  a  selected  lot  of  the  population,  selected  because  of  their 
physiological  and  bio-chemical  inadequacy  to  meet  the  situation  presented  by 
germs  of  disease  in  the  body. 

Resistance  to  disease  is  a  subject  that  has  been  studied  more  in  plants, 
perhaps,  than  in  animals.  In  any  case,  it  is  recognized  of  great,  practical 
importance  by  plant  and  animal  breeders.  By  proper  methods  of  breeding 
there  have  been  produced  all  sorts  of  agricultural  crops  which  are  resistant  to 
smuts,  rusts  and  wilts.  Similarly,  there  are  strains  of  domestic  animals  which 
have  been  bred  resistant  to  cholera,  as  in  hogs,  to  certain  protozoan  diseases, 
as  in  poultry  and  the  like.  In  humans  no  attempt  has  been  made  to  breed 
resistant  strains;  nevertheless  there  are  known  lines,  or  strains,  which  are 
highly  resistant  to  diseases.  This  resistance  is  shown  by  the  fact  that  the 
individuals  of  such  lines  are  rarely  ill  and  that  they  often  live  to  an  advanced 
age.  Such  nonagenarians  are  resistant  not  only  to  the  ordinary  germs  of 
disease,  but  also  to  the  degenerative  diseases  which  make  their  appearance 
during  the  involutionary  period.  That  longe\aty  is  inherited  is  clear  from 
families  that  every  observer  can  cite,  and  that  are  often  described  in  the 
literature.  The  fact  has  also  been  repeatedly  demonstrated  statistically,  be- 
ginning with  the  very  full  studies  made  by  Alexander  Graham  Bell  some 
twenty  years  ago.  Besides  a  natural  immunity  and  resistance  there  is,  of 
course,  acquired  immunity,  but  this  again  is  a  familial  trait.  Persons  must 
already  have  a  certain  amount  of  resistance  in  order  to  acquire  immunity  to 
possibly  fatal  disease;  were  there  no  such  initial  resistance,  there  would  be  no 
opportunity  to  build  up  such  immunity. 

Vol.  I.  934 


512     HEREDITY  AND   EUGENICS   IN   RELATION  TO  MEDICINE 

The  Allergies  and  Vitamin  Insufficiencies 

During  the  present  century  there  has  developed  a  clear  knowledge  of  the 
anaphylactic  reaction  and  of  the  allergies  which  are  associated  with  it.  It  has 
also  become  clear  that  the  allergic  reactions  are  highly  specific  in  their  inci- 
dence, that  while  in  certain  families  there  is  a  wide-spread  tendency  toward 
hay  fever  or  eczema  following  inhalation  of  certain  proteins  or  the  ingestion 
of  particular  foods,  other  families  are  quite  immune  to  such  irritating  agents. 

As  for  vitamin  insufficiencies,  a  study  that  was  made  at  the  Eugenics 
Record  Office  of  the  incidence  of  pellagra  in  Spartansburg,  S.  C.  showed  very 
clearly  that  the  disease  ran  a  virulent  course  only  in  certain  families  and,  in- 
deed, in  cases  where  severe  effects  followed,  these  were  of  different  type  in 
different  families.  There  were  families  characterized  principally  by  dermal 
symptoms,  others  by  intestinal  symptoms,  others  by  symptoms  of  the  central 
nervous  system. 

Similarly,  the  ability  to  resist  the  insufficiency  of  particular  vitamins  seems 
to  vary  in  different  individuals,  and  this  difference  probably  has  a  genetical 
basis.  There  are  some  persons  more  tolerant  of  insufficiency  of  vitamins  A  or 
B,  for  example,  than  are  others. 

Twin  Production 

The  number  of  simultaneous  ovulations  in  a  single  female  differs  greatly  in 
different  animals  running  all  the  way  from  the  condition  in  oysters  where  a 
hundred  million  eggs  may  be  laid  simultaneously  to  the  condition  found  in 
many  mammals  and  particularly  in  groups  of  primates  where  usually  only  one 
or  two  eggs  are  ovulated  at  the  same  time.  In  humans  about  one  labor  in  loo 
results  in  twins,  about  one  in  10,000  in  triplets,  the  higher  numbers  being 
relatively  much  rarer  still.  The  tendency  toward  twin  production  depends 
upon  the  constitution  of  the  parents.  It  is  necessary,  of  course,  for  twin 
production  that  two  eggs  should  be  simultaneously  ovulated,  but  of  such 
simultaneous  ovulation  only  a  small  proportion  give  rise  to  twins.  This  follows 
from  some  studies  made  many  years  ago  by  Leopold,  who  found  that  about 
ID  per  cent,  of  women's  ovaries  showed  two  recent  corpora  lutea  and,  therefore, 
two  recent  double  ovulations.  Although,  as  stated,  only  i  per  cent,  of  labors 
are  twin-producing,  the  discrepancy  between  a  10  per  cent,  ovulation  and  a  i 
per  cent,  twin  birth  is  to  be  ascribed  in  part  to  the  male.  Indeed,  there 
have  been  published  a  number  of  observations  indicating  that  the  male  is 
not  less  responsible  for  the  production  of  twins  than  the  female  consort.  The 
explanation  of  the  deficiency  is  in  part  the  failure  of  both  eggs  to  be  fertilized, 
but  even  more  important  is  the  failure  of  a  certain  proportion  of  the  eggs  to 

Vol.  I.  934 


THE   INTERNAL  SECRETIONS   AND   CONSTITUTION         513 

develop  far  in  utero.  Such  intrauterine  deaths,  which  amount  to  from  40  per 
cent,  to  75  per  cent,  in  strains  of  mice,  seem  to  be  due  not  to  any  pathological 
condition  in  the  uterus  but  to  the  presence  of  lethal  factors  in  the  genes  of  the 
germ  cells.  If  both  parents  carry  the  same  lethal  factors,  then  the  egg  will 
develop  only  a  little  way.  If  one  parent  only  brings  in  the  lethal  factor,  the 
child  may  develop  inadequately  in  the  organs  affected,  and  early  intrauterine 
death  may  be  expected.  A  heavy  rate  of  twin  production  is  found  where  there 
is  multiple  ovulation  and  where  the  male  is  vigorous  and  produces  sperm  that 
is  without  lethal  factors. 

The  importance  of  constitution  in  twin  production  is  indicated  by  the 
frequent  cases  of  particular  mothers  who  produce  twins  repeatedly.  One  of  the 
most  striking  cases  (which  is,  moreover,  very  well  documented)  is  that  of  Mrs. 
Clark  of  Cleveland,  who  by  three  different  husbands  had  a  total  of  forty-two 
children  born  over  a  period  of  less  than  30  years,  beginning  at  the  age  of  about 
fourteen.  During  this  period  she  averaged  nearly  three  children  at  a  birth, 
never  had  a  single  child  at  a  time,  in  six  instances  had  triplets  and  in  four 
instances  quadruplets.  By  her  first  husband  she  had  only  one  pair  of  twins, 
by  her  second,  two  sets  of  twins  and  two  sets  of  triplets;  by  her  third  husband 
the  size  of  litter  produced  has  averaged  much  higher.  It  is  to  be  noted  that 
according  to  the  best  information  available  her  mother  had  only  twins,  triplets 
and  quadruplets,  and  her  grandmother  in  turn  is  stated  to  have  had  many 
multiple  births.  However,  the  earlier  generations  were  not  seen,  since  they 
lived  in  France. 

The  hereditary  tendency  to  twin  production  has  been  followed  not  only  in 
humans  but  also  in  sheep.  Dr.  Alexander  Graham  Bell  was  able  by  careful 
selection  of  twin  breeders,  both  on  the  male  and  female  side,  to  greatly  increase 
the  proportion  of  twins  and  triplets  produced.  From  that  strain,  on  one 
occasion,  quadruplets  developed  in  the  uterus,  but  caused  the  death  of  the 
mother,  since  she  was  unable  to  give  birth  to  them. 

The  Internal  Secretions  and  Constitution 

The  importance  of  the  internal  secretions  has  become  increasingly  recog- 
nized during  the  present  century.  Hereditary  factors  have  been  discovered 
for  a  number  of  the  endocrine  conditions.  One  of  the  most  striking  has  been 
studied  in  mice  by  Dr.  E.  C.  MacDowell.  A  particular  strain  of  highly  inbred 
mice  produced  litters  containing  dwarfs.  Investigation  showed  that  the  dwarfs 
had  rudimentary  anterior  lobes  of  the  pituitary  gland.  Associated  with  this 
were  an  inactive  thyroid  gland  and  suprarenals  of  which  the  cortex  was  quite 
inactive.  The  gonads  of  these  animals  also  functioned  inadequately.  By 
injecting  into  the  dwarfs  the  hormones  from  normal  pituitaries  the  growth  of 

Vol.  I.  934 


514    HEREDITY  AND   EUGENICS   IN  RELATION  TO  MEDICINE 

the  sterile  dwarfs  was  promoted;  they  became  nearly  normal  in  size,  and  they 
also  became  sex-functional.  Autopsies  revealed  that  the  thyroids  and  supra- 
renal cortex  had  become  active,  though  the  anterior  lobes  still  remained  rudi- 
mentary. In  this  strain  of  mice  the  dwarfism  appeared  to  be  due  to  a  single 
recessive  gene.  Similar  studies  by  Riddle  and  Benedict  have  shown  that  in 
particular  strains  of  pigeons  the  activity  of  the  thyroid  gland,  as  measured  by 
basal  metabolism  is  high,  in  other  strains  it  is  low.  In  general,  the  develop- 
mental defects  which  are  due  to  endocrine  disfunction  may,  in  turn,  be  ascribed 
to  a  more  remote  genie  defect  which  is  responsible  for  that  disfunctioning. 
This  genie  defect  passes  down  through  the  generations. 

One  of  the  most  striking  of  the  endocrine  effects  has  to  do  with  the  build 
of  the  body.  Body-build  runs  the  whole  gamut  of  possibilities  from  very  slen- 
der to  very  fleshy  and  obese.  These  conditions  of  build  are  believed  to  be 
highly  influenced,  if  not  controlled,  by  endocrine  conditions.  To  be  sure,  within 
limits,  body  build  may  be  influenced  by  food  intake.  On  the  other  hand, 
certain  strains  will  not  tolerate  excessive  food  intake  and,  consequently,  re- 
main slender.  Studies  made  at  the  Eugenics  Record  Office  on  inheritance  of 
body-build  indicate  that  there  are  two  or  more  genes  responsible  for  the  result; 
that  where  both  parents  are  slender  the  children  are  tv^Dically  slender,  that 
where  both  parents  are  fleshy  the  children  are  mostly  fleshy,  but  some  of  them 
may  be  of  intermediate  or  slender  build.  The  pituitary  and  the  thyroid  both 
influence  body  build,  and  perhaps  other  endocrine  glands  do  also.  Since  the 
anterior  pituitary  gland  influences  the  growth  processes  and  also  the  develop- 
ment of  the  gonads,  insufhciencies  in  the  activity  of  this  gland  result  in  indi- 
viduals who  are  overweight  and  in  whom  (especially  the  male)  the  secondary 
sex  characters  are  underdeveloped. 

There  seems  to  be,  also,  as  Kretschmer  pointed  out  many  years  ago,  a 
certain  relation  between  body  build  and  form  of  psychoses.  Thus,  in  those 
individuals  in  which  the  psychosis  is  of  dementia  praecox  type,  the  individuals 
are  prevailingly  of  a  slender,  "asthenic"  type,  whereas  in  the  manic-depressive 
psychosis  the  victim  has  a  robust,  "pyknic"  build.  Extensive  studies  have 
been  made  upon  body  build  in  relation  to  psychoses.  Kretschmer's  findings  have 
been  repeatedly  confirmed.  However,  the  work  which  has  been  done  has  been 
for  the  most  part  non-quantitative.  The  studies  of  Wertheimer  (1926),  done  in 
association  with  Dr.  Adolph  Meyer  of  Johns  Hopkins  University,  lead  to  the  con- 
clusion that  this  relation  of  constitution  to  psychoses  has  been  exaggerated. 

The  failure  of  the  secretions  from  the  islands  of  Langerhans  of  the  pan- 
creas is  now  known  to  be  an  important  factor  in  the  production  of  diabetes, 
but  numerous  studies  have  shown  this  to  have  a  hereditary  factor,  as  for 
example  those  of  Gossage  (1908),  of  Williams  (191 7),  Pincus  and  White  in 
Joslin's  clinic  (1933),  and  others. 

Vol.  I.  934 


ABNORMAL   GROWTHS  515 

Abnormal  Growths 

All  vertebrates,  and  particularly  man,  are  subject  to  extraordinary  localized 
growths  in  the  body,  especially  of  the  adult.  While  it  is  well  known  that 
certain  families  are  especially  apt  to  form  these  tumors,  still  the  method  of 
inheritance  has  not  been  definitely  ascertained  in  the  case  of  humans,  and  it  is 
certainly  particularly  compUcated  by  the  random  mating  of  humans.  Light 
upon  the  factors  responsible  for  tumor  growth  is  thrown  by  studies  made  by 
Dr.  E.  C.  MacDowell  on  leukemia  in  mice.  In  a  strain  of  mice,  highly  inbred, 
brother  and  sister  for  forty  generations,  there  appeared  some  individuals  that 
died  of  a  disease  diagnosed  as  leukemia.  These  were  all  traced  back  to  a  single 
mother  in  a  line  known  in  the  laboratory  as  C58.  When  the  leukemic  cells 
from  a  mouse  progressed  in  the  disease  were  inoculated  into  an  unaffected 
mouse  of  this  strain,  even  before  the  ordinary  age  of  incidence  of  leukemia,  the 
inoculated  mouse  died  usually  within  a  week.  If,  however,  some  of  the  same 
inoculant  was  put  into  mice  of  another  strain,  such  as  that  known  in  the 
laboratory  as  SL,  there  was  only  a  slight  reaction  at  the  point  of  inoculation, 
but  no  tumor  was  formed,  or  if  a  slight  tumor  appeared,  it  quickly  vanished. 
It  was  obvious  that  the  "soil"  was  dififerent  in  the  m.ice  of  this  particular 
strain  of  C58  and  in  the  SL  strain,  and  that  the  soil  of  the  latter  did  not 
permit  the  growth  of  the  leukemic  cells.  If  a  mouse  of  the  SL  strain 
be  mated  with  one  of  the  C58  strain,  then  the  offspring  are  susceptible  and 
further  studies  indicate  that  a  single  factor  is  responsible  for  the  susceptibility. 
This  fairly  clean-cut  result  was  possible  because  of  the  nature  of  the  inbreeding 
to  which  the  mice  had  been  subjected,  and  in  consequence  of  which  they  had 
become  genetically  nearly  "pure."  Naturally,  in  the  young  of  mice  bred 
haphazardly  one  can  not  predict  the  susceptibility,  and  indeed  all  susceptible 
mice  would  probably  prove  to  be  heterozygous  and  produce  susceptible  as  well 
as  resistant  individuals.  This  latter  condition  is  exactly  the  one  we  find  in 
humans  where  resistant  and  non-resistant  strains  have  been  combined  for  an 
indefinite  number  of  generations,  and  tw^o  susceptible  genes  from  the  two 
parents  will  only  occasionally  come  together  in  the  fertilized  egg,  or  the 
"zygote."  It  is  probably  on  this  account  that  statisticians  have  not  been  able 
to  show  an  inheritance  of  a  tendency  toward  tumor  growths  between  parents 
and  children.  Nevertheless,  the  evidence  is  clear  not  only  from  the  case  of 
MacDowell's  mice,  but  from  other  confirmatory  evidence,  that  there  is  such  a 
thing  as  natural  resistance  to  tumor  growth  and  natural  susceptibility.  What- 
ever the  factor  is  that  gives  resistance,  whether  a  particular  enzyme  or  other 
factor,  is  not  as  yet  known.  It  is,  of  course,  quite  possible  that  one  might 
build  up  a  resistance  to  tumor  growth  in  an  organism  by  appropriate  technique. 
Among  tumors  whose  inheritance  has  been  more  or  less  well  studied  are  the 

Vol.  I.  934 


5i6    HEREDITY  AND   EUGENICS   IN  RELATION  TO  MEDICINE 

following:    multiple  neurofibromatosis,  in  which  the  susceptibility  is  dominant, 
also  multiple  telangiectases  and  polyadenomata  of  the  rectum. 

Skin  diseases  that  are  likewise  inherited  as  dominant  traits  are  epidermolysis 
bullosa,  ichthyosis,  keratosis,  and  persistent  hereditary  edema.  All  of  these 
skin  tumors  may,  on  occasion,  pass  into  malignant  sarcoma,  which  thus  shows 
again  its  hereditable  basis. 

Skin  Diseases 

A  large  number  of  skin  defects  and  diseases,  such  as  albinism,  birth  marks 
(naevus),  keratosis,  psoriasis,  anonychia,  hypotricosis,  seborrhoea,  have  been 
shown  to  depend  upon  hereditary  factors.  Usually  there  is  a  dominant  factor 
responsible  for  the  defect.  The  evidence  for  inheritance  of  diseases  of  the  skin 
has  been  presented  by  W.  H.  Siemens  in  a  large  number  of  papers.  Heavy 
pigmentation  in  the  skin  was  found  in  the  negro  race  dominant  over  light 
pigmentation  as  in  Europeans;  apparently  there  are  two  (double)  factors 
responsible  for  the  deeper  pigmentation.  The  mulattoes  have  only  one  (double) 
factor  and  quadroons  only  one.  The  tendency  to  early  baldness,  which  has 
been  regarded  by  many  as  simply  an  accidental  disease,  has  been  shown  to  be 
inherited  as  apparently  a  sex-limited  character.  The  baldness  tends  to  run  in 
different  families  in  particular  t\'pes,  and  some,  or  all,  of  these  types  are  found 
as  specific  characters  in  dilTerent  species  of  primates,  as  Gerrit  S.  Miller  points 
out.  Scar  tissue  reacts  differently  in  different  races  of  mankind,  forming 
keloid  tumors  in  negroes. 

Skeletal  System 

The  development  of  bone  is  a  complicated  process  that  has  a  long  phylo- 
genetic  history  reflected  in  its  complicated  nature.  Especially  the  long  bones 
are  subject  to  great  variation  depending  upon  the  activity  of  certain  genes  that 
are  responsible  for  their  full  development.  Sometimes  the  bones  are  formed  in 
abnormal  fashion,  as  for  example  in  brittle  bones  where  the  Haversian  canals 
are  improperly  formed,  or  absent.  Inheritance  of  this  condition  has  been 
described  in  Bulletin  14  of  the  Eugenics  Record  Office.  In  other  cases  the 
long  bone  fails  of  expected  linear  development.  The  consequence  is  that  the 
legs  and  arms  are  abnormally  short,  as  one  sees  in  achondroplastic  dwarfs. 
Inheritance  of  dwarfism  has  been  described  in  the  "Treasury  of  Human  In- 
heritance" by  Rischbieth  and  Barrington,  and  reference  is  made  to  that  publi- 
cation for  further  details. 

The  number  of  digits  is  subject  to  hereditary  abnormalities.  Thus  in 
poultry  and  the  lower  mammals  the  number  may  be  reduced  to  4  or  3,  and  in 

Vol.  I.  934 


MUSCULAR   SYSTEM  517 

other  cases  increased  to  6,  or  more.  Always  in  these  cases  there  is  a  dominant 
factor  which  interferes  with  the  normally  precise,  definite  number  of  digits 
formed  on  the  margin  of  the  paddle  at  the  tip  of  the  embryonic  limb;  in  other 
cases  the  bones  of  adjacent  fingers  may  be  grown  together  producing  the  con- 
dition known  as  syndactylism.  This  is  found  also  in  poultry.  The  phenomenon 
has  been  treated  monographically  in  the  "Memoirs  of  the  Galton  Laboratory 
of  Eugenics"  Part  6.  Even  the  details  of  forms  of  hand  and  feet  are  modifiable 
by  hereditary  factors.  Such  modifications  arise  as  crooked  fingers,  double 
jointedness,  and  variations  in  the  relative  length  of  the  first  and  second  digits 
of  the  foot  and  the  second  and  fourth  of  the  hand. 

The  bones  of  the  hand  are  especially  liable  to  defects;  thus  ankylosis  of  the 
phalanges  has  been  repeatedly  described.  A  defect  of  this  sort  has  been  traced 
by  Gushing  through  seven  generations  in  the  United  States  and  by  Drink- 
water  through  fourteen  generations.  A  related  defect  is  brachydactylia,  ab- 
normalities of  length  of  the  metacarpal  bones.  The  fourth  metacarpal  seems 
to  be  especially  apt  to  develop  imperfectly,  possibly  due  to  an  imperfect  de- 
velopment of  the  distal  epiphysis.  In  the  formation  of  the  carpal  bones  heredi- 
tary factors  govern,  as  shown  by  J.  W.  Pryor,  who  has  traced  the  order  of 
development  of  carpal  bones  in  single  members  of  various  families.  When  the 
order  of  development  of  the  carpal  bones  differ  in  one  and  the  same  families 
there  is  apt  to  be  a  resemblance  in  these  sequences  of  development. 

The  form  of  the  skull  is  a  racial  characteristic  and  details  in  size  and  pro- 
portions of  the  head  are  notoriously  found  in  families.  The  heredity  of  the 
cephalic  index  has  been  studied  by  G.  P.  Frets. 

Muscular  System 

While  the  muscular  system  probably  has  been  less  completely  studied  from 
a  genetical  point  of  view  than  the  other  systems  of  the  body,  yet  to  it  have 
been  ascribed  inherited  deviations  from  type.  For  example,  the  suppression  of 
the  palmaris  longus  muscle  of  the  fore  arm  apparently,  is  inherited  as  a  domi- 
nant. Its  absence  is  more  frequent  in  Europeans  than  in  Negroes.  Numerous 
abnormalities  are  due  to  defects  in  the  nerves  that  innervate  the  particular 
muscles.  Thus,  peroneal  atrophy  has  been  described  in  extensive  families  as, 
for  example,  by  Macklin  and  Bowman,  1926,  in  loi  descendants  of  an  emi- 
grant to  Canada.  This  defect  behaves  as  a  dominant.  The  most  extensive 
study  of  myotonic  epilepsy,  which  shows  the  symptoms  of  spasms  in  various 
muscles,  has  been  afforded  by  Lundborg,  1913,  who  described  2,232  indi- 
viduals in  seven  generations.  The  disease  is  inherited  as  a  MendeHan  recessive. 
Myotonic  distrophy,  waste  of  muscles  owing  to  nervous  defect,  takes  on  vari- 
ous forms  which  are  apt  to  be  found  to  be  repeated  in  families  where  an  at- 

VOL.  I.   934 


5i8    HEREDITY  AND   EUGENICS   IN   RELATION  TO   MEDICINE 

tempt  is  made  to  trace  them.  Hereditary  tremors  have  been  described  in 
animals,  as  for  example  by  Riddle  in  pigeons,  where  46  aiJected  individuals 
occurred  in  a  particular  strain.  Large  pedigrees  have  been  secured  for  human 
families  by  a  number  of  authors.  Finally  small  muscular  deviation,  such  as 
produce  face  dimples,  show  clear  dependence  upon  hereditary  factors. 

Nervous  System 

Above  all  other  systems  of  organs,  the  control  of  the  nervous  system  by 
hereditary  factors  is  of  the  greatest  moment  to  human  society  and  to  the 
progress  of  civilization,  for,  the  constitution  of  the  nervous  system,  and  its  re- 
actions to  internal  secretions  and  to  other  bodily  conditions,  determines  con- 
duct, behavior,  and  to  a  large  extent  the  interaction  of  man  on  man  and  race 
on  race.  These  hereditary  nervous  factors  determine  emotions  and  aspirations, 
and  the  control  or  absence  of  control  of  instincts  and,  consequently,  the  indi- 
vidual's fitness  as  a  social  being. 

That  the  development  of  the  brain  with  its  accompanying  intellectual 
capacity  is  determined  by  the  absence  of  one  or  more  factors  that  make  for 
normal  development  has  been  shown  again  and  again  in  the  innumerable 
studies  that  have  been  made  upon  the  feeble-minded.  A  great  many  families 
have  been  studied  in  which  feeble-mindedness  occurs  in  a  high  percentage  of 
cases,  and  the  results  published  by  Goddard  (Kalikaks),  Danielson  and  Daven- 
port (hill  folk),  Estabrook  (Nam  family  and  the  Jukes),  Finlayson  (Dack 
family)  and  many  others.  Such  strains  with  mental  defect  are  particularly 
apt  to  be  found  in  less  highly  developed  communities,  such  as  occur  in  some 
mountain  valleys.  The  isolation  in  these  parts  is  apt  to  lead  to  consanguineous 
marriages  and  in  consequence,  in  such  strains,  to  a  large  proportion  of  feeble- 
mindedness due  to  the  same  factor  or  factors.  When  both  parents  are  feeble- 
minded, typically  all  of  the  children  are  feeble-minded  also,  though  some 
exceptions  occur  where  the  feeble-mindedness  is  due  to  different  types  of  defect. 

Often  associated  with  feeble-mindedness  is  the  tendency  toward  epileptic 
convulsions  of  the  degenerating  type,  a  tendency  which  shows  itself  usually  at 
adolescence.  Studies  of  this  subject  have  been  published  in  the  Eugenics 
Record  Office  Bulletin,  191 1,  and  by  Romer  and  by  Hermann.  In  the  typical 
institutional  cases  the  epileptic  symptoms  seem  to  be  due  to  the  absence  of  a 
factor  that  makes  for  nervous  control.  Tendency  to  migraine  has  also  a  clear 
genetic  factor  in  many  cases,  and  there  is  a  remarkable  concurrence  of  it  with 
epilepsy  in  certain  families. 

All  types  of  functional  insanity  seem  to  depend  upon  genetical  defects. 
Of  these  dementia  praecox  has  been  studied  most  carefully  from  a  genetical 
point  of  view  by  Riidin  and  co-workers.  This  depends  apparently  upon  the 
Vol.  I.  934 


NERVOUS   SYSTEM  519 

absence  of  a  genetical  factor  that  prevents  mental  deterioration  and  schizo- 
phrenia following  the  incidence  of  mental  assaults.  While  for  many  Freudians 
the  exogenous  factor  is  alone  to  be  considered,  yet  the  high  incidence  of  dementia 
prsecox  in  particular  families  and  its  entire  absence  in  others  not  less  well 
protected  from  such  untoward  conditions  demonstrates  that  the  constitution 
of  the  individual  must  also  be  considered. 

In  case  of  depressive  insanity  it  is  probable  that  more  than  one  factor  is 
involved.  There  is  reason  for  thinking  that  the  lack  of  control  which  shows 
itself  in  great  emotional  output  and  excitability  under  comparatively  slight 
stimulus  is  partly  due  to  the  presence  of  some  genetical  factor  which  inhibits 
self-control,  while  depressions  are  due  partly  to  the  absence  of  certain  genetical 
factors  that  are  essential  to  calmness  under  ordinary  circumstances.  Again, 
the  tendency  to  dipsomania,  nymphomania,  pyromania,  and  the  other  ob- 
sessive neuroses,  seem  to  be  due  to  the  absence  of  particular  genetical  factors 
responsible  for  control.  Dipsomania  seems  to  be  dependent  upon  a  sex- 
linked  factor  shown  only  by  males,  but  transmitted  through  daughters.  In  studies 
on  crime  we  are  apt  to  look  exclusively  to  exogenous  factors,  such  as  bad  com- 
panions. A  broad  view  of  the  matter  requires  us  to  consider  also  the  constitu- 
tional factors  in  which  certain  individuals  find  agreeable  the  stimulus  derived 
from  such  bad  associations.  In  crime  we  must  look  not  only  at  the  conditions 
under  which  it  was  performed,  but  also  to  the  nature .  of  the  individual  whose 
behavior  was  so  bad.  In  the  case  of  the  nomadic  trait,  which  is  found  in 
vagrants,  as  well  as  sometimes  in  persons  of  wealth  and  culture,  there  is  much 
evidence  that  this  is  inherited  as  a  sex-linked  trait  (Bulletin,  Eugenics  Record 
Office,  No.  12,  1915). 

Among  the  more  strictly  nervous  diseases  the  history  of  Huntington's  chorea 
has  been,  perhaps,  more  completely  worked  out  than  any  other.  It  has  been 
possible  to  trace  this  disease  in  certain  of  our  families  through  ten  generations, 
and  to  show  the  way  in  which  the  germ  plasm  carrying  the  defect  has  migrated 
from  Southern  New  England  and  Long  Island  to  upper  New  York  State, 
Vermont,  Ohio,  Michigan,  Wisconsin,  Kansas,  Nebraska,  California,  Oregon,  and 
other  parts  of  the  United  States  (Bulletin,  Eugenics  Record  Office,  No.  17, 
1916). 

It  is  impossible  in  available  space  to  go  into  details  concerning  all  of  the 
nervous  diseases  which  have  a  genetical  basis.  Speech  defects,  such  as  stutter- 
ing and  stammering,  have  been  shown  by  Bryant,  Estabrook  and  others  to 
recur  in  strikingly  high  incidence  in  particular  families.  Numerous  paralyses 
of  special  organs,  some  of  which  have  been  referred  to  in  the  chapters 
on  "Muscular  System"  have  repeatedly  been  shown  to  have  hereditary 
bases. 

That  tendency  to  self-destruction  has  a  genetical  basis  is  sufficiently  demon- 

VOL.  I.   934 


520    HEREDITY  AND   EUGENICS   IN  RELATION  TO  MEDICINE 

strated  by  the  tendency  to  recurrence  in  particular  families,  and  even,  in  them, 
of  a  particular  type.  This  matter  has  been  discussed  by  Davenport  in  Carnegie 
Institution  Publication  No.  236.  Sometimes  the  tendency  to  suicide  is  a  strong 
impulse,  generally  associated  with  manic  temperament,  and  is  thus  of  the  type 
of  a  dominant  trait.  In  other  cases  the  suicide  occurs  in  deep  depression,  and 
such  depressions  are  associated  with  a  recessive  condition,  as  mentioned 
above. 

Not  only  those  abnormalities  in  the  nervous  system  and  its  output  which 
society  regards  as  defects,  but  also  those  other  nervous  and  mental  peculiarities, 
which  are  commonly  spoken  of  as  special  gifts,  show  the  hereditary  factor. 
Though  this  is  not  a  matter  primarily  of  medical  interest,  still  attention  may 
be  called,  in  passing,  to  the  evidence  of  inheritance  in  the  factors  that  make 
great  fighters,  great  mathematicians,  great  musicians,  great  writers,  painters, 
explorers,  missionaries,  clergy,  physicians  and  the  rest. 

Sense  Organs 

The  eye  is  subject  to  scores  of  defects  in  the  course  of  its  development,  and 
the  hereditary  recurrence  in  particular  families  of  these  defects  has  long  at- 
tracted the  attention  of  ophthalmologists.  The  most  recent  bibliography  of 
these  defects  is  that  prepared  by  the  late  Lucien  Howe,  published  as  Bulletin 
No.  21  of  the  Eugenics  Record  Office.  The  Hst  indicates  which  of  these  are 
inherited  as  dominant,  which  are  recessive,  and  which  are  sex-linked.  Of 
course,  the  method  of  inheritance  of  many  of  these  traits  is  more  complex, 
depending  on  two  or  more  factors.  Great  advances  in  our  knowledge  of  in- 
heritance of  eye  defects  have  been  made  by  A.  Vogt  of  Zurich,  and  findings  in 
this  field  have  been  summarized  recently  by  P.  J.  Waardenburg. 

Ever  since  Alexander  Graham  Bell  published  his  "Deaf  Variety  of  the 
Human  Race"  (Memoir  of  the  National  Academy  of  Sciences,  1883),  it  has 
been  clear  that  certain  forms  of  deafness  depend  upon  hereditary  factors. 
However,  deafness  is  not  a  biological  entity,  but  only  a  symptom.  It  may 
depend  upon  various  genetical  factors.  The  genetical  background  probably  is 
often  complex.  It  is  necessary  to  distinguish  sporadic  congenital  deafness  and 
deafness  occasioned  by  syphilis.  The  latter  is  of  the  nature  of  an  accident,  while 
the  former  depends  upon  genes.  One  type  of  deafness,  otosclerosis,  is  primarily 
a  bone  defect,  but  functionally  belongs  to  the  present  category.  Otosclerosis, 
or  progressive  hereditary  hardness  of  hearing,  is  due  to  abnormal  osteogenic 
changes  in  the  otic  capsule  and  the  margins  of  the  fenestra  ovalis  (which  is 
closed  by  the  base  of  the  stapes),  so  that  the  stapes  is  firmly  ankylosed  in  such 
fashion  that  vibrations  are  no  longer  conducted  by  the  auditory  ossicles,  but 
better  directly  through  the  bones  of  the  head.     Genetic  factors  in  otosclerosis 

Vol.  I.  934 


RESPIRATORY  SYSTEM  520  (i) 

have  been  recently  studied  through  support  from  the  Otosclerosis  Committee  of 
the  American  Otological  Society  by  C.  B.  Davenport,  Bess  Lloyd  Milles, 
and  Lillian  B.  Frink,  whose  results  appear  in  the  Archives  of  Otolaryngology, 
19^3.  Heredity  is  complex,  depending  on  two  or  possibly  more  pairs  of  fac- 
tors. 

Idiosyncracies  of  taste  have  been  discovered  recently  and  found  to  have  a 
hereditary  basis,  by  Snyder  and  by  Blakeslee,  (both  1931).  For  example, 
phenyl-thio-carbamide  gives  a  bitter  sensation  in  some  human  strains,  in  others 
none  at  all. 


Alimentary  System 

Within  the  last  few  years  evidence  has  accumulated  of  the  familial  basis  of 
some  of  the  defects  in  the  food  canal  and  its  adnexa.  Very  obvious  is  the  re- 
currence of  inheritance  of  harelip  and  cleft  palate  in  families.  The  inheritance, 
however,  is  complex.  This  matter  has  been  well  analyzed  by  J.  Sanders 
(1934);  dominant  inheritance  has  been  found  through  twelve  or  more  genera- 
tions. 

Numerous  studies  have  shown  that  there  is  a  genetical  basis  for  gastric 
and  duodenal  ulcers.  A  hypersensibility  of  the  intestinal  mucosa  to  chemical 
and  mechanical  irritation  has  been  described  by  Jiingling  (1928).  The  tendency 
to  production  of  gall  stones  is  also  one  which  depends  upon  a  hereditary  chemi- 
cal constitution. 

Respiratory  System 

That  there  are  hereditary,  or  racial,  factors  present  in  the  mucous  mem- 
branes of  the  nasopharynx  there  can  be  no  doubt.  Indeed,  Undritz  (1928) 
concludes  that  inheritance  is  the  rule  rather  than  the  exception  in  oto-rhino- 
laryngological  diseases.  It  is  notorious  that  among  colored  persons  there  is  a 
relative  resistance  to  diseases  that  enter  the  body  through  the  nasopharyngeal 
portals,  which  are  so  ill  defended  among  whites.  Adenoids,  tonsillitis  and  diph- 
theria are  much  less  common  in  our  colored  population  than  in  whites,  despite 
the  superior  sanitation,  on  the  whole,  of  the  latter  race  in  this  country. 

In  respect  to  the  pneumonias  it  is  clear  that  their  onset  is  due  to  a  reduc- 
tion in  bodily  resistance.  In  different  human  strains  there  is  much  variation 
in  this  natural  immunity,  and  one  finds,  as  Pearl  has  demonstrated,  that 
tendency  to  pneumonia  is  a  familial  tendency.  To  be  sure,  both  conditions  of 
Ufe  preceding  the  disease  and  age  play  an  important  part  in  the  incidence  of 
pneumonia,  but  back  of  all  of  these  is  the  variability  in  ability  to  resist  the 
multiplication  of  the  pneumococcus  germs. 

Vol.  I.  934 


520(2)    HEREDITY  AND   EUGENICS   IN  RELATION  TO  MEDICINE 

Circulatory  System 

The  heart  and  blood  vessels,  the  blood  itself,  are  all  markedly  under 
the  control  of  hereditary  factors.  There  have  been  described  families  where  the 
children,  at  birth,  are  m.ore  or  less  cyanotic,  with  imperfect  development  of  the 
valves  of  the  heart.  A  case  is  described  by  O.  Bourwinkel  (1910).  There  is 
reason  for  beheving  that  a  tendency  toward  degeneration  of  the  walls  of  the 
arteries,  as  well  as  hy'per tension,  depend  upon  constitutional  factors.  A  chap- 
ter on  heredity  of  arteriosclerosis  has  been  published  in  a  book  on  that  subject 
by  the  Josiah  Macy,  Jr.  Foundation. 

Hemophilia,  which  depends  upon  the  absence  of  the  enzyme  largely  re- 
sponsible for  the  production  of  the  clotting  elements  of  the  blood,  has  been 
shown  repeatedly  to  run  in  families  in  a  sex-linked  fashion.  One  may  conclude 
that  the  enzyme  responsible  for  this  clotting  is  in  this  sex  chromosome.  In 
affected  families  the  males  alone  show  the  condition,  but  do  not  transmit  it  to 
their  sons,  as  they  transmit  no  sex  chromosomes  to  the  sons,  but  they  do 
transmit  the  affected  chromosomes  to  their  daughters,  who  show  no  symptoms, 
and  these  daughters  may  transmit  the  defect  to  their  sons. 

Variations  in  the  elements  of  the  blood  stream  are  numerous,  and  some  of 
these  have  been  shown  to  have  a  hereditary  basis.  The  inheritance  of  tendency 
toward  leukemia,  or  a  great  excess  of  the  white  blood  corpuscles,  has  been  al- 
ready described.  Families  with  pernicious  anemia  have  been  described  by  O. 
Schaumann,  (1918),  and  other  Scandinavian  authors.  Similarly,  polycythemia 
has  been  traced  through  generations  by  E.  Engelking,  (1920). 

Summary 

The  above  review  of  diseases  and  defects  shows  sufficiently  that  the  heredi- 
tary factors  present  must  always  be  looked  for,  even  though  these  diseases  may 
never  occur  without  the  presence  of  a  particular  microorganism,  for  the 
microorganisms  can  not  be  regarded  as  the  sole  and  effective  cause  of  these 
diseases  or  defects.  We  must  believe  that  the  constitutional  factors  prepare  the 
soil,  and  the  nature  of  the  soil  determines  the  nature  of  the  harvest,  that  is,  the 
symptoms,  which  the  seed  sown  upon  it  will  produce.  The  medical  man,  who 
neglects  in  his  consideration  of  diseases  and  defects  the  genetical  factors,  will 
never  succeed  completely  in  accounting  for  the  phenomena  with  which  he  has 
to  deal.  Heredity  is  not  something  occasional  and  special.  Heredity  deter- 
mines the  very  nature  of  the  organism,  both  the  normal  organism  and  the 
organism  that  deviates  from  the  normal.  Only  pathologists  who  are  willing  to 
admit  that  there  is  a  disease  apart  from  the  diseased  organism  can  decline  to  con- 
sider the  man  as  well  as  the  parasite  that  is  one  of  the  factors  in  producing  disease. 
Vol.  I.  934 


APPLIED   EUGENICS  520  (3) 

III.   APPLIED   EUGENICS 

Now  that  we  know  that  the  development  of  the  physical,  mental  and  emo- 
tional traits  of  man,  his  resistance  to  disease  and  his  normal  functioning  are 
determined  very  largely  by  heredity,  it  follows  that  reasonable  human  beings 
should  act  in  accordance  with  this  knowledge.  Our  social  difficulties  are  largely 
due  to  the  presence  in  our  population  of  feeble-minded,  or  paranoiacs,  of  those 
lacking  social  instincts,  of  those  with  little  control  over  the  emotions.  Our 
present  methods  of  dealing  with  these  social  disturbers  are  various.  In  a 
primitive  society  we  may  punish,  scorn,  or  pity  the  individuals,  according  to  our 
individual  nature,  but  these  reactions  do  little  to  solve  our  problem.  More 
effective  is  the  segregation  of  such  persons  for  a  longer  or  shorter  period,  but 
it  is  the  custom  eventually  to  return  such  segregated  individuals  after  some 
years  of  training  to  the  community.  Since  their  constitution  has,  however,  not 
been  altered  they  will  tend  to  return  to  their  anti-social  conduct.  By  releasing 
segregated  individuals  at  a  time  when  the  reproduction  urge  is  strong  we  per- 
mit the  reproduction  of  their  traits. 

An  appreciation  of  the  danger  of  reproducing  inherently  defective  germ 
plasm  has  led  many  of  our  states,  and  other  countries,  to  attempt  to  exercise 
some  control  over  this  reproduction.  All  states  have,  indeed,  recognized  their 
right  and  duty  to  attempt  to  control  matings.  Thus  we  have  laws  against  the 
mating  of  the  feeble-minded,  epileptic,  insane,  of  cousins,  and  of  inter-marriage  be- 
tween different  races  (Eugenics  Record  Office  Bulletin  No.  9).  These  laws  have, 
however,  primarily  a  legal  import  rather  than  a  eugenic  one,  and  moreover  they 
are  inadequately  enforced.  Something  could  be  done  to  improve  present  con- 
ditions, if  a  greater  control  were  exercised  over  matings  by  parents,  or  older 
persons,  as  is  done  more  satisfactorily  in  other  countries  than  in  ours.  In  the 
absence  of  other  adequate  control  of  matings  many  states  have  found  it  ad- 
vantageous to  put  on  the  statute  books  laws  permitting  sterilization  of  the 
genetically  defective.  Over  one-half  of  the  states  of  the  Union  have  had  such 
laws  in  the  past;  at  present  about  twenty- two  of  the  states  carry  them.  Of  all 
these  states,  California  has  performed  more  sterilizations  than  any  other.  Up 
to  1929,  indeed,  6,225  sterilizations  had  been  performed  in  the  California  State 
Hospitals,  and  1,488  in  institutions  for  the  feeble-minded.  In  Canada,  Switzer- 
land, Denmark,  Germany,  and  some  other  countries,  sterilization  laws  are  in 
effect.  There  has  been  some  question  as  to  the  social  consequences  of  the 
releasing  into  the  general  population  of  sterilized  individuals.  The  evidence, 
however,  indicates  that  such  sterilized  persons  do  not  become  the  focus  of 
immorality.  The  whole  social  aspect  of  sterilization  is  treated  adequately  by 
E.  S.  Gosney  and  Paul  Popenoe  in  their  book  "Sterilization  for  Human  Better- 
ment," (1929).    Statistics  concerning  sterilization  in  different  states  have  been 

Vol.  I.  934 


520(4)    HEREDITY  AND   EUGENICS   IN  RELATION  TO  MEDICINE 

published  by  H.  H.  Laughlin  in  Eugenics  Record  Office  Bulletins,  and  else- 
where, and  sterilization  is  more  and  more  becoming  recognized  not  as  a  punitive 
but  as  a  eugenic  measure. 

The  prohibition  of  marriages  between  cousins  has  been  placed  upon  the 
statute  books  of  over  one-third  of  the  states  in  the  Union  (Eugenics  Record 
Office  Bulletin  No.  9,  1913).  Apparently  the  laws  have  been  thus  passed 
because  of  the  experience  of  legislators  with  particular  cases  in  which  defective 
offspring  have  arisen  from  such  close  matings.  Such  legislation  does  not  seem 
to  be  in  accord  with  our  present  biological  knowledge.  It  has  now  been  demon- 
strated by  geneticists,  that  cousin  marriage  per  se  does  not  lead  to  defective 
offspring.  However,  on  the  one  hand  it  increases  the  incidence  of  defective 
offspring,  where  there  is  gross  recessive  defect  in  the  common  stock,  as  for 
example,  feeble-mindedness,  epilepsy  and  other  types  of  insanity.  On  the  other 
hand,  cousin  marriage  is  a  very  valuable  means  of  perpetuating  and  even 
increasing  the  general  developmental  vigor  of  the  children  where  the  common 
stock  is  without  such  gross  defect.  The  case  of  Charles  Darwin,  who  married 
his  first  cousin,  Emma  Wedgwood,  and  produced  five  sons  who  became  leaders 
in  science,  invention,  and  economics  in  Great  Britain,  is  a  case  in  point.  The 
remarkable  group  of  Walcotts  and  their  kin,  in  Connecticut,  which  furnished  a 
long  line  of  Governors  of  the  state  of  Connecticut,  were  the  product  of  cousin 
marriages.  To  make  use  of  our  knowledge  of  genetics  in  such  legislation,  it 
were  better  to  provide  that  a  marriage  between  cousins  should  not  be  permitted 
without  a  certificate  from  a  state  Eugenics  Board,  after  an  examination  of  the 
pedigree,  to  make  sure  that  there  is  no  gross  hereditary  defect  in  the  common 
stock. 

Since  the  health  and  happiness  of  the  United  States  depend  so  much  upon 
the  predominance  of  the  physically,  mentally  and  emotionally  fit  stock,  the  state 
may  well  inquire  into  the  relative  fertility  of  the  most  effective  and  the  least 
effective  strains.  At  this  time  throughout  civihzed  countries,  and  particularly 
in  America,  through  voluntary  limitation  of  the  size  of  families,  the  most  suc- 
cessful stock  is  not  reproducing  itself  in  anything  like  the  proportion  of  the 
less  successful  stock.  The  sons  of  Harvard  University  have  only  about  0.8  of 
a  son,  on  the  average,  while  the  daughters  of  Wellesley  have  even  a  smaller 
proportion  of  daughters.  Into  a  population  which  is  strictly  not  reproducing 
itself  there  has  entered  a  strong  propaganda  for  the  dissemination  of  "birth 
control"  information.  Were  it  possible  through  the  spread  of  such  information 
to  diminish  the  relatively  greater  fertility  of  the  less  effective  stock,  the  propa- 
ganda would  be  biologically  advantageous.  The  birth  controllist,  however, 
early  found  that  the  less  effective  and  thrifty  stratum  did  not  respond  to  the 
propaganda  for  reduction  in  size  of  families;  for  the  parents  in  such  stratum 
each  child  was  regarded  as  an  economic  asset.     The  birth  controUists  there- 

VOL.  I.    934 


APPLIED   EUGENICS  520  (5) 

upon  carried  their  propaganda  into  tiie  higher  social  stratum,  which  was  al- 
ready reducing  the  size  of  families  to  a  minimum,  with  the  idea  that,  were  their 
teachings  effective  in  the  higher  levels,  a  fashion  would  become  established 
which  would  become  adopted  in  the  lower  levels.  There  is,  however,  as  yet  no 
satisfactory  evidence  that  the  propaganda  is  working  out  in  any  other  way 
than  to  encourage  the  more  thrifty  to  diminish  still  further  the  number  of  their 
children.  Thus,  it  may  well  be  that  the  birth  control  propaganda  in  this  coun- 
try is  diminishing  the  proportion  of  the  more  effective  children  born.  It 
would  seem  desirable  rather  to  encourage  the  more  effective  stock  to  have 
larger  families  than  to  extend  more  widely  the  principles  of  restriction  of 
reproduction.  Such  stimulus  might  be  given  on  the  one  hand  by  appealing  to 
higher  ideals  and,  on  the  other,  in  economic  ways,  by  reducing  taxation  and 
inheritance  levies  in  proportion  to  the  number  of  children  in  the  familv. 

A  predominance  of  the  fit  will  not  be  maintained  merely  by  increasing  the 
number  of  offspring  but  also  by  increasing  the  number  who  survive  to  marry, 
and  in  turn  become  progenitors.  An  intelligent  society  will,  therefore,  do  its 
utmost  to  encourage  the  survival  of  its  fittest  strains  and  will  be  more  con- 
cerned therein  than  in  securing  the  survival  of  the  children  of  inferior  strains. 
The  appeal  sometimes  made  by  social  workers  for  funds  to  diminish  the  mor- 
tality rate  of  children  of  lowest  social  and  intellectual  level  may  well  fail  to 
arouse  enthusiastic  response. 

Control  of  matings  and  of  fertility  is  only  part  of  the  problem  of  securing 
the  highest  proportion  of  effective  persons  in  the  population.  Until  recent 
years  the  matter  of  immigration  has  been  of  importance  in  connection  with 
this  aim.  In  the  early  years  of  our  immigration  there  was  little  selection  of 
immigrants,  and  it  was  possible  for  European  countries  to  exile  to  the  United 
States  those  convicted  of  minor  offenses  and  even  sometimes  of  important 
crimes.  Also,  attempts  were  made  to  bring  large  numbers  of  the  cheapest 
labor  from  Europe,  and  even  from  Asia,  to  help  develop  our  resources.  Im- 
portation from  Asia  was  early  put  a  stop  to.  Only  recently  has  a  marked 
restriction  been  made  on  immigration  from  the  lowest  economic  stratum  of 
Europe.  Today  we  exclude  the  feeble-minded  and  the  criminalistic.  For  the 
moment  the  whole  problem  of  immigration  to  the  United  States  has  become 
less  important,  owing  to  the  fact  that  the  United  States  has  become  an  old 
country  and  is  already  well  filled.  Our  resources  have  become  more  than 
adequately  exploited,  so  that  the  country  offers  less  lure  to  the  prospective 
immigrant.  At  the  same  time  the  opening  of  large  areas  in  South  America 
and  the  better  economic  outlook  there  is  diverting  the  stream  from  the  United 
States  to  that  continent.  If,  and  when,  the  immigration  tide  sets  again  towards 
North  America,  it  is  to  be  hoped  that  an  adequate  selection  will  be  made  of 
such  immigrants  to  insure  the  highest  possible  quality  of  our  future  citizenship. 

Vol.  I.  934 


52o(6)    HEREDITY  AND   EUGENICS   IN   RELATION  TO  MEDICINE 

Recognition  of  the  fact  of  heredity  does  not  render  unnecessary  efforts  that 
have  been  made  toward  education  and  moral  and  religious  culture.  Even 
plants,  to  yield  their  best  fruit,  must  be  cultivated,  and  the  innate  good  traits 
of  children  may  be  repressed  by  a  "bad"  environment.  Eugenics,  however, 
teaches  that  it  is  as  futile  to  try  to  train  the  feeble-minded  boy  to  be  a  scholar 
as  it  is  to  try  by  cultivation  to  make  a  golden  bantam  variety  of  corn  into  a 
giant.  Our  efforts  toward  education  will  be  more  effective  when  we  recognize 
first  that  children  are  all  different,  and  when  we  seek,  secondly,  to  develop  to 
the  utmost  those  germs  of  desirable  traits  that  they  possess,  and,  thirdly,  to 
repress  undesirable  tendencies.  So  also  in  matters  of  health  the  physician 
must  recognize  that  all  of  his  patients  are  different,  and  he  must  urge,  there- 
fore, different  hygienic  training  in  accordance  with  individual  needs.  It  is 
sometimes  said  that  eugenics  is  a  medical  matter,  and  so  it  is,  indeed,  but  it  is 
also  a  social  matter  of  the  highest  import.  It  is  for  physicians  and  those 
interested  in  social  welfare  and  social  development  to  unite  in  applying  the 
principles  of  eugenics  to  the  advancement  of  the  State. 

The  facts  of  heredity  may  be  well  called  upon  to  aid  in  certain  legal  pro- 
cedures, especially  in  determination  of  disputed  paternity.  Insofar  as  the  laws 
of  inheritance  of  traits  have  become  definitely  established,  they  can  be  utilized 
to  advantage  in  such  disputed  cases.  For  example,  the  established  principle 
that  two  parents,  both  of  whom  produce  no  melanic  pigment  in  their  irides 
can  have  only  children  with  the  same  trait,  may  be  used  to  decide  matters  of 
disputed  parentage,  or  to  decide  whether  a  given  claimant  for  an  estate,  on 
the  ground  of  relationship  to  his  alleged  parents,  has  a  just  claim.  Valuable 
in  this  connection  is  the  fact  of  inheritance  of  the  factors  that  cause  iso-agglu- 
tination  of  the  blood.  It  appears  that  the  red  blood  cells  of  many  persons 
produce  an  enzyme  called  "agglutinogen,"  which  leads  to  the  production  in 
the  serum  of  the  blood  of  corresponding  "agglutinins."  The  commonest  of  the 
agglutinogens  that  are  known  are  designated  as  A,  B,  and  the  corresponding 
agglutinins  in  the  serum  are  designated  as  a,  b.  If  now  the  blood  of  a  person, 
who  carries  in  the  cells  agglutinogen  A,  be  mixed  with  the  serum  from  a  person 
with  agglutinogen  B  and,  therefore,  with  the  agglutinin  b,  then  the  blood 
cells  derived  from  this  individual  tend  to  clump  in  the  drop.  On  this  account 
it  is  important,  in  the  case  of  blood  transfusions,  to  secure  a  donor  of  the  same 
blood  group  as  the  person  into  whose  veins  the  blood  is  to  be  injected;  other- 
wise agglutination  will  occur,  and  through  consequent  blocking  of  the  blood 
vessels  serious  effects,  and  even  death,  may  follow.  Besides  the  two  types  of 
persons  who  produce  agglutinogens  A  or  B  there  is  a  third  type  that  produces 
both  agglutinogens  A  and  B  and  corresponding  agglutinins  a  and  b.  Finally, 
there  is  a  fourth  group  which  produces  no  agglutinogens.  Such  persons  can  re- 
ceive infusion  with  impunity.     Now,   if  a  given  child  belongs  to   the  group 

Vol.  I.  934 


APPLIED   EUGENICS  520  (7) 

with  agglutinogen  A  in  the  blood,  and  its  known  parent  belongs  to  the  group 
which  produces  agglutinogen  B,  then  it  must  be  that  the  other  parent  belongs 
to  the  group  which  produces  agglutinogen  A,  or  to  the  group  that  produces  the 
two  agglutinogens  A  and  B.  Similarly,  a  child  that  produces  agglutinogen  B 
and  whose  known  parent  produces  only  agglutinogen  A,  or  produces  no  agglu- 
tinogen, must  have  had  as  its  other  parent  one  belonging  to  the  group  of  B, 
or  A  B.  The  table  describing  all  the  possibilities  for  the  unknown  parent  of 
disputed  children  wich  particular  blood  groups  is  given  in  treatises  treating  of 
the  blood  groups  of  which  may  be  mentioned  that  of  L.  H.  Snyder. 

The  facts  of  heredity  may  be  advantageously  used  in  other  matters  of 
social  importance,  such  as  giving  advice  in  respect  to  the  choice  of  a  profession. 
Specifically,  we  may  answer  the  question  whether  a  given  boy  would  probably 
succeed  as  a  physician  or  surgeon.  It  is  necessary  before  such  advice  can  be 
given  to  consider  the  distribution  in  the  family  tree  of  high  degree  of  success 
in  the  given  profession.  We  do  not  know  just  how  the  different  traits,  which 
are  responsible  for  success  in  a  given  profession,  are  inherited.  We  do  know, 
however,  that  in  some  cases,  as  in  medicine  and  surgery,  striking  cases  of 
outstanding  success  in  three,  four,  or  more,  generations  are  known.  This  would 
seem  to  suggest  that  there  is  at  least  one  essential  factor  in  such  success  which 
is  inherited  as  a  dominant  trait. 

To  the  psychiatrist  a  knowledge  of  family  history  of  patients  is  of  vast 
importance,  and  this  fact  is  so  generally  known  that  family  histories  are  now 
regularly  taken  in  the  best  developed  institutions.  The  late  Dr.  E.  E.  South- 
ard, of  Boston,  stated  that  he  would  hardly  diagnose  with  confidence  a  case  of 
manic  depressive  insanity  whose  family  history  showed  no  other  individuals 
who  might  fall  into  the  same  category.  It  is  important,  however,  that  the 
psychiatrist  should  not  depend  for  knowledge  of  the  family  merely  upon  testi- 
mony of  relatives  who  accompany  the  patient  to  the  hospital,  since  for  social 
reasons  such  relatives  tend  to  minimize  the  importance  of  the  genetical  factor, 
and  to  cover  up  striking  cases  of  similar  defect  in  the  family.  Accordingly, 
many  institutions  find  it  advantageous  to  employ  field  workers  who  can  be  sent 
to  the  homes  from  which  the  patients  come,  in  order  to  make  first  hand  obser- 
vations and  inquiries  concerning  the  traits  of  other  members  of  the  family. 

Instead,  as  is  so  often  done,  of  regarding  heredity  as  a  dour  doctrine  and 
one  whose  conclusions  are  fatalistic  and  opposed  to  the  program  of  human 
improvement  that  is  being  promoted  by  sociologists  and  ph}-sicians,  it  were 
better  to  look  upon  heredity  as  a  power  for  social  regeneration  of  the  first 
importance.  Every  farmer  recognizes  the  incalculable  value  of  heredity  in  the 
production  of  his  best  stocks.  He  controls  his  matings  with  the  greatest  care, 
since  he  knows  that  the  value  of  the  next  generation  will  depend  upon  such 
matings.     It  is  to  be  hoped  that  in  time,  in  civilized  countries,  it  will  be  ap- 

VOL.  I.    934 


52o(8)    HEREDITY  AND   EUGENICS  IN  RELATION  TO  MEDICINE 

predated  that  the  future  of  the  country  depends  especially  on  the  quality  of 
the  germ-cells  that  are  being  transmitted  to  future  generations.  If  these 
germ-cells  determine  the  development  of  individuals  of  the  highest  quality,  they 
become  invaluable.  One  sees  vast  sums,  amounting  to  even  hundreds  of  thou- 
sands of  dollars,  that  are  spent  for  particular  animals,  such  as  the  horse  or  the 
bull,  to  be  used  for  breeding  purposes.  The  money  is  not  spent  for  muscle  or 
bone,  but  for  the  literally  microscopic  enzymes  that  are  carried  in  the  germ 
cells.  If  all  the  enzymes  that  were  used  in  reproduction  should  be  brought 
together,  they  would  still  be  beyond  the  limits  of  visibility  or  of  weighing. 
For  the  possession  of  such  invisible  materials  persons  are  willing  to  stake  a 
fortune.  If  the  enzymes  for  successful  race  horses,  or  for  great  milk  producing 
cows  are  of  such  value,  how  much  more  should  we  treasure  the  germ-plasm  in 
our  population  that  is  responsible  for  the  most  valuable  social  qualities. 

July  I,  1934. 


Vol.  T.  934 


CHAPTER  XII-A 

ALBINISM 

By  FREDERICK  R.  TAYLOR 

Table  of  Contents 

Synonyms 520  (10) 

Definition 520   (10) 

History 520   (10) 

Etiology  and  Pathogenesis 520   (11) 

Symptomatology 520   (12) 

Diagnosis 520   (14) 

Prognosis  and  Treatment 520  (14) 

Bibliography 520   (15) 

Synonyms.  —  Albinismus,  congenital  leukopathia,  congenital  leuko- 
derma, congenital  leukasmus,  congenital  achromia,  dyschroia,  moon-eyes, 
children  of  the  sun   (Guatemala). 

Definition.  —  Albinism  is  a  congenital  condition  which,  in  its  complete 
form,  is  characterized  by  a  total  lack  of  the  melanin  group  of  pigments  in 
the  body,  its  striking  features  in  man  being  a  lack  of  pigment  in  the  skin, 
hair  and  eyes,  with  resulting  photophobia,  nystagmus,  high-grade  refrac- 
tive errors  and  extreme  susceptibility  of  the  skin  to  strong  sunlight  and 
other  potent  sources  of  ultra-violet  radiation.  Other  body  pigments,  not 
included  in  the  melanin  group,  such  as  lipochromes,  urochromes,  blood 
and  bile  pigments,  etc.,  are  present.  Incomplete  and  partial  forms  of 
albinism  occur.  Albinism  is  found  widely  distributed  throughout  the 
animal  kingdom,  and  an  analagous  condition  due  to  absence  of  plant 
pigments  occurs  in  the  vegetable  world. 

History 

While  albinism  has  doubtless  existed  from  a  very  early  period  in 
the  life  of  man,  references  to  it  in  ancient  literature  seem  surprisingly 
scant  for  such  a  striking  condition.  Lagleyze  of  Buenos  Aires,  who  prob- 
ably has  given  the  most  exhaustive  discussion  of  the  subject  in  the  litera- 
ture, states  that  a  passage  in  the  Elder  Pliny's  writings  seems  to  indicate 

COPYRIGHT  1937   BY  THE  OXFORD  UNIVERSITY  PRESS.  NEW  YORK,  INC. 

520  (9) 


520  (lo)  ALBINISM 

that  he  had  seen  a  case  of  albinism,  and  that  Hernando  Cortes  is  said  to 
have  mentioned  albinos  at  the  court  of  Montezuma.  There  seems  to 
have  been  little  general  scientific  interest  in  albinism,  however,  before  the 
1 8th  century,  when  many  accounts  of  the  condition  by  various  travelers 
appeared,  notably  the  early  explorers  in  Africa,  who  reported  albinism  in 
Guinea,  Algeria,  Madagascar  and  along  the  Congo.  Lagleyze  tells  us  that 
in  1704  Wafer  described  albinos  in  Panama.  Apparently  albinism  was 
not  generally  recognized  in  the  white  race  until  very  recent  times,  for  La- 
gleyze says  that  in  1774  DePaul  stated  that  albinism  did  not  exist  in 
Europe  and  that  it  was  found  only  within  ten  degrees  of  the  equator. 
However,  ten  years  later  Blumenbach  described  some  albinos  at  Chamonix 
in  the  Alps  and  apparently  was  the  first  to  attribute  the  red  light  in  the 
pupil  and  the  apparent  color  of  the  iris  to  their  true  cause.  During  the 
past  century  albinism  has  been  reported  in  all  races  from  practically  all 
parts  of  the  world,  though  its  frequency  varies  greatly  in  different  localities. 

Of  special  interest  to  the  ethnologist  are  the  varying  attitudes  of  primi- 
tive peoples  towards  albinos.  Often  persecuted  or  killed,  albinos  have 
been  objects  of  veneration  in  some  places,  especially  where  they  are  rare. 
Certain  negro  tribes  represent  the  devil  as  having  a  white  skin.  In 
Guinea  albinos  have  been  considered  sacred  and  invulnerable,  in  Sene- 
gambia,  as  possessed  of  evil  spirits,  in  Uganda  they  were  wondered  at  as 
curiosities  and  kept  about  the  kings.  According  to  Lagleyze  on  the  island 
of  Parrot  in  the  mouth  of  the  Calabar  River  in  West  Africa,  the  natives 
sacrificed  an  albino  child  to  the  god  of  the  whites  when  no  European 
merchant  ship  had  called  in  a  long  time. 

Among  many  interesting  primitive  beliefs  regarding  albinos  may  be 
noted  the  following:  that  they  are  born  of  women  impregnated  by  goril- 
las; that  they  are  born  of  women  who,  while  asleep  in  the  forest,  were 
impregnated  by  meteors;  that  the  morning  star  is  the  father  of  all  al- 
binos;   that  the  devil  is  their  real  father. 

Lagleyze  quotes  Dubois  as  stating  that  in  certain  parts  of  India  the 
natives  used  to  draw  and  quarter  albinos  and  throw  their  bodies  on 
manure  piles  or  to  ferocious  beasts. 

Etiology  and  Pathogenesis 

Little  is  known  of  the  etiology  of  albinism  other  than  that  it  is  a  con- 
genital defect  in  the  mechanism  which  gives  rise  to  the  melanin  group  of 
pigments  in  the  body.  For  many  years  a  battle  raged  over  the  question 
of  the  etiologic  significance  of  heredity,  many  authorities  denying  its 
influence,  but  the  weight  of  opinion  today  regards  albinism  as  a  Mendelian 

Vol.  I.  937 


ETIOLOGY   AND    PATHOGENESIS  520(11) 

recessive  characteristic.  Mudge,  Jablonski,  Pardo-Castello  and  Musser, 
among  others,  definitely  subscribe  to  this  view.  Musser  explains  the 
relative  rarity  of  albinism  by  the  fact  that  the  health  of  albinos  usually  is 
poor,  and  they  often  die  without  propagating.  Swab  records  the  case  of  a 
white  man  who  married  a  negress;  they  had  a  black  daughter;  when 
she  became  15  years  old,  her  father  had  incestuous  relations  with  her,  and 
an  idiot  albino  resulted.  Wakefield  and  Dellinger  have  described  a  pair 
of  albino  identical  twins  of  negro  parentage.  A  view  formerly  held,  that 
albinism  represents  an  atavistic  reversion  to  a  special  race  of  albinos,  has 
been  practically  abandoned.  Consanguinity  in  the  parents  seems  to  pre- 
dispose somewhat  to  albinism.  Lagleyze  studied  27  albinos  in  13  families; 
among  these  13  albinos  in  5  families  had  consanguineous  parents.  The 
27  comprised  the  total  number  of  albinos  he  had  seen  among  30,000 
patients.  In  no  case  did  an  albino  child  have  an  albino  parent.  In  addi- 
tion to  his  own  cases,  Lagleyze  studied  the  data  on  48  families  in  the 
literature,  with  220  children,  104  of  whom  were  albinos.  In  10  of  these 
families  the  parents  were  stated  to  be  consanguineous  without  mention 
of  albinotic  heredity,  in  7  albinism  was  reported  in  collateral  antecedents, 
in  5  there  was  no  mention  of  familial  factors. 

Garrod  suggests  three  possibilities  to  explain  the  pathogenesis  of  al- 
binism, as  follows:  (i)  a  structural  peculiarity  of  the  cells  which  renders 
them  incapable  of  pigmentation;  (2)  an  absence  of  the  material  from 
which  melanin  is  formed;  (3)  the  lack  of  a  specific  enzyme  which  brings 
about  the  formation  of  melanin. 

A  number  of  observations  seem  to  support  the  last  hypothesis  at  the 
expense  of  the  first  two,  among  which  are  the  following. 

Mudge  noted  that  in  albino  rats  immersion  in  formalin  turned  the 
hairs  a  vivid  yellow.  Subsequent  immersion  in  hydrogen  peroxide  turned 
them  a  brownish  color.  He  believes  that  this  proves  the  presence  of  a 
chromogen  and  indicates  the  absence  of  a  ferment  in  albinism  that  nor- 
mally converts  the  chromogen  into  pigment.  He  quotes  Cuenot  as  sug- 
gesting that  the  pigmentation  of  mammalian  hair  is  due  to  the  interaction 
of  a  chromogen  and  a  ferment.  He  also  cites  the  work  of  Miss  Durham, 
who  extracted  in  water  from  the  skins  of  young  rodents  a  material 
which,  when  incubated  with  tyrosin  to  which  a  small  quantity  of  ferrous 
sulphate  had  been  added  as  an  activator,  threw  down  a  pigment  of  the 
same  colc)r  as  that  of  the  hair  growing  out  of  that  particular  portion  of 
skin.  Mudge  also  notes  that  breeding  experiments  show  that  albinos 
carry  some  pigment  factors.  Mudge's  findings  were  confirmed  by  Sollas. 
Schultz  showed  that  a  piece  of  albinotic  rabbit  skin  containing  growing 
hair,  when  kept  for  from  seven  to  twelve  hours  under  certain  conditions  of 

Vol.  I.  937 


520  (i2)  ALBINISM 

moisture  and  oxygen  at  a  temperature  of  from  30°  to  36°  C,  would 
develop  a  strong  melanin  pigment  at  the  hair  roots.  By  a  similar  method 
the  iris  of  a  newborn  albino  rabbit  became  pigmented. 

Garrod  calls  attention  to  some  interesting  findings  of  several  investi- 
gators as  follows:  Halliburton,  Brodie  and  Pickering  noted  that  intraven- 
ous injections  of  nucleoproteins  in  albino  animals  failed  to  produce  such 
clotting  as  in  pigmented  ones.  Mudge  found  that  all  albino  rabbits  were 
not  alike  in  this  respect,  but  that  in  general  more  nucleoprotein  must  be 
injected  into  albino  animals  to  cause  death  from  intravascular  clotting 
than  into  similar  pigmented  controls.  Pickering  also  noted  that  the  Nor- 
way hare  in  its  winter  coat  reacts  like  an  albino  when  injected  with 
nucleoprotein,  whereas  in  summer  it  reacts  like  any  other  pigmented 
animal.  Bickel  and  Tasawa  found  that  exposure  for  several  weeks  to  a 
bright  light  increased  the  red  cell  count  in  pigmented  animals  but  did  not 
do  so  to  any  appreciable  degree  in  albinos. 

Symptomatology 

Complete  albinism  presents  the  following  symptoms  and  physical  signs. 
The  skin  is  milky  white  and  looks  thin  and  delicate.  The  superficial  blood 
vessels  are  conspicuous.  The  hair  is  fine  and  almost  white,  of  a  very  pale 
silvery  flax  color.  The  irides  are  untinted  and  appear  red,  pink  or  violet 
according  to  the  intensity  of  the  light  by  which  they  are  seen,  looking  red 
in  a  very  strong  light  and  violet  in  a  very  subdued  one.  There  is  a  red 
pupil  reflex  due  to  the  lack  of  pigmentation  within  the  eyes,  which  re- 
semble those  of  a  white  rabbit.  Because  of  the  lack  of  protective  pigment 
in  the  eyes,  photophobia  is  marked,  and  nystagmus  is  an  almost  constant 
finding.  The  latter  usually  develops  in  early  infancy,  though  occasionally 
it  is  present  at  birth.  As  a  rule,  it  is  horizontal,  rapid  and  of  wide  ex- 
cursion, though  rotary  and  mixed  forms  have  been  described.  Lagleyze 
explains  the  nystagmus  as  an  effort  of  the  eyes  to  escape  from  the  irri- 
tating light.  The  nasal  side  of  the  eye  being  more  shaded  than  the  tem- 
poral, the  eyes  move  back  and  forth  in  an  eflfort  to  relieve  the  points  of 
momentary  maximum   irritation. 

The  extreme  photophobia  develops  a  characteristic  attitude  and  facies 
in  which  the  head  is  bent  forward,  the  eyes  are  kept  partially  closed, 
there  is  a  constant  frown,  and  in  a  strong  light  the  patient  will  nearly 
always  shield  his  eyes  with  a  hand  as  with  a  vizor,  unless  they  are  suit- 
ably protected.  The  pressure  on  the  eyeballs  from  the  contracting 
muscles  is  considerable,  and  this  soon  gives  rise  to  a  high  degree  of  re- 
fractive error,  which  may  be  hyperopic  or  myopic,  and  is  always  com- 

VoL.  I.  937 


SYMPTOMATOLOGY  520  (13) 

plicated  by  a  very  marked  astigmatism.  Chronic  blepharitis  naturally 
is  the  rule.  In  addition  the  visual  acuity  becomes  markedly  reduced 
and  usually  is  found  to  be  from  3^^  to  Ko  of  the  normal.  This  is  a 
true  amblyopia  which  remains  after  refractive  correction.  AH  these 
phenomena  tend  to  make  the  albino  look  abnormally  old.  Often  the  optic 
discs  appear  about  the  same  color  as  the  rest  of  the  eyegrounds,  which 
are,  of  course,  pale  and  can  be  found  only  by  locating  the  entrance  and 
exit  of  the  retinal  vessels.  In  other  cases  they  may  appear  a  deep  red  or 
an  ashy  gray.  Color  vision  and  the  visual  fields  are  unaffected.  Lagleyze 
has  noted  persistence  of  the  pupillary  membrane  in  a  few  albinos  and 
states  that  he  has  not  seen  it  in  non-albinos.  Concomitant  strabismus 
often  occurs  in  albinism.  Shaad  noted  that  albinos  adapt  their  vision  to 
relative  darkness  less  rapidly  than  normal  persons,  but  their  vision  be- 
came more  sensitive  in  the  dark  after  10  minutes  than  that  of  normal  con- 
trols and  remained  so  throughout  the  remainder  of  a  30  minute  test. 
The  name  "moon-eyes",  sometimes  applied  to  albinos,  is  based  on  the 
fact  that  they  can  see  better  by  moonlight  than  by  bright  daylight. 

Intelligence  is  unaffected  by  albinism.  All  grades  of  intelligence  from 
idiocy  to  brilliance  have  been  noted,  as  in  non-albinos. 

The  skin  will  not  tan  in  the  sun  and  is  very  susceptible  to  sunburn 
and  irritation  from  other  types  of  ultra-violet  radiation.  Garrod  states 
that  melanotic  tumors  do  not  occur  in  the  albino,  and  that  there  is  no 
record  of  an  albino  with  Addison's  disease.  The  hyperpigmented  areas 
usual  in  pregnancy  do  not  appear  in  albino  women.  Hewer  reports  three 
cases  of  multiple  epitheliomata  in  Egyptian  albinos  which  he  considers 
due  to  the  action  of  the  sun's  rays  on  the  unpigmented  skin. 

A  number  of  associated  anomalies  have  been  noted  in  individual 
albinos,  but  these  probably  are  to  be  looked  on  as  coincidental,  rather 
than  as  bearing  any  relation  to  the  albinism.  The  writer  has  studied  a 
case  of  albinism  in  a  young  woman,  a  virgin,  who  had,  in  addition  to  a 
severe  dysmenorrhea,  a  practically  complete  congenital  absence  of  the 
muscles  of  the  pelvic  floor,  the  vaginorectal  septum  being  almost  as  thin 
as  paper. 

Albinism  may  be  classified  as  complete,  incomplete  and  partial.  The 
complete  form  has  been  discussed.  Incomplete  albinism  is  a  condition  in 
which  there  is  a  general  deficiency,  but  not  complete  absence  of  the 
melanin  pigments.  There  are  all  grades  of  this,  with  corresponding 
degrees  of  severity  of  symptoms. 

In  partial  albinism  there  are  contrasting  albinotic  and  normal  areas 
throughout  the  body.  If  an  eye  is  in  an  albinotic  area,  it  will  be  affected, 
otherwise  it  will  not.     Only  a  portion  of  an  eye  may  be  involved.     Hair 

Vol.  I.  937 


520  (h)  albinism 

growing  out  of  albinotic  areas  is  devoid  of  pigment,  that  growing  out  of 
normal  areas  has  the  normal  color.  A  number  of  instances  of  red  haired 
albinos  have  been  recorded.  Garrod  states  that  the  pigment  may  be 
present  in  the  eyes  alone,  in  which  case  the  other  ocular  phenomena  of 
albinism  are  likely  to  be  absent.  Squire  reported  the  case  of  an  albino, 
whose  entire  skin  and  hair  system  were  pigmentless,  but  whose  eyes  were 
dark  blue,  who  had  no  photophobia,  but  who  did  have  horizontal  nystag- 
mus, so  that  he  had  difficulty  in  reading,  though  his  visual  acuity  was 
normal. 

A  piebald  appearance  often  occurs  in  partial  albinism  and  prob- 
ably represents  a  mosaic  inheritance.  Pardo-Castello  regarded  all  such 
cases  as  probably  achromic  nevi.  Traub,  however,  has  given  us  a  dif- 
ferential criterion,  viz.,  that  piebald  albinotic  areas  become  hyperemic  on 
friction  with  ice,  whereas  achromic  nevi  do  not.  Firth  has  made  the 
interesting  observation  that  individual  red  hairs  from  the  scalp  of  a  black 
haired  African  showed  the  same  characters  as  the  hairs  do  in  red  haired 
albinos. 

Diagnosis 

Diagnosis  of  albinism  usually  is  obvious  on  inspection.  Occasionally 
partial  albinism  may  have  to  be  differentiated  from  achromic  nevi  by 
Traub's  method  as  described  above.  Vitiligo  is  distinguished  from  partial 
albinism  by  the  fact  that  it  is  an  acquired  condition,  whereas  partial 
albinism  is  congenital. 

Prognosis  and  Treatment 

Garrod  states  that  albinos  occasionally  may  acquire  pigmentation  in 
childhood  or  early  life.  The  condition  usually  is  permanent,  however. 
Poor  health  due  to  the  eyestrain  and  to  various  other  associated  condi- 
tions often  occurs,  so  that  the  life  expectancy  of  an  albino  probably  is 
less  than  that  of  a  normal  person  of  the  same  age. 

Treatment  is  largely  a  matter  for  the  ophthalmologist,  who  must  be 
consulted  for  protection  of  the  eyes  from  light  and  for  proper  refraction. 
The  piebald  cases  may  benefit  from  dermatologic  advice,  as  certain  stains 
have  been  devised  for  use  on  the  pigmentless  areas  for  cosmetic  pur- 
poses. In  such  cases  the  recently  introduced  "Covermark"  also  might 
prove  helpful.  Strong  light  should  be  avoided  and  special  precautions 
taken  against  sunburn.  Exposure  of  the  body  to  other  forms  of  potent 
ultra-violet  radiation  also  is  contraindicated. 

Vol.  I.  937 


BIBLIOGRAPHY  520  (15) 

BIBLIOGRAPHY 
FIRTH,  D.:    Red-headed  albinos,  Proc.  Roy.  Soc.  Med.,  1924,  (Clin.  Sect.),  XVII, 

25- 

FOLKER,  W.  H.:    Case  of  a  remarkable  albino.  Lancet,  1879,  I,  795. 

GARROD,  A.  E. :  Inborn  Errors  of  Metabolism,  p.  30,  2nd  ed.,  Henry  Frowde  and 
Hodder  and  Stoughton,   Lond.,   1923. 

GOULD,  G.  M.:  The  pernicious  influence  of  albinism  upon  the  eye.  Jour.  Am.  Med. 
Assoc,   1893,  XXI,  685. 

GUNN,  A.  R.:   Albinism  in  man,  Brit.  Med.  Jour.,  1907,  I,  718. 

HEISER,  V.  G.  and  VILLAFRANCA,  R.:  Albinism  in  Philippine  Islands,  Philip- 
pine Jour.  Sci.,  1913,  VIII,  493. 

HEWER,  T.  F. :  Multiple  epitheliomata  in  albino,  Brit.  Jour.  Dermat.  and  Syph., 
1932,  XLIV,  469. 

JABLONSKI,  \V. :  Ueber  Albinismus  des  Auges  im  Zusammenhang  mit  den  Verer- 
bungsregeln,  Deutsch.  med.  Wchnschr.,  1920,  XLVI,  708. 

LAGLEYZE:    L'oeil  des  albins,  Arch.  d'Opht.,  1907,  XXVII,  280,  361,  461. 

McLEOD,  J.  M.  H.:  Complete  albinism  in  a  girl  aged  6,  with  total  absence  of  pig- 
ment in  the  skin,  hair,  choroid  and  iris,  Proc.  Roy.  Soc.  Med.,  1910-11,  IV, 
Dermat.  Sect.,  7. 

MUDGE,  G.  P.:  Problems  in  Mendelism  and  some  biological  considerations:  hu- 
man albinos.  Lancet,  1909,  I,  857;  Jour.  Physiol.,  1909,  XXXVIII,  (Proc. 
Physiol.  Soc,  March  27,  1909,  p.  Ixvii). 

MUSSER,  J.  H.,  Jr.:  Albinism  in  the  negro,  Med.  Clin.,  North  America,  1924, 
VIII,  7S1. 

PARDO-CASTELLO,  V.:  Congenital  partial  albinism.  Arch.  Dermat.  and  Syph., 
1926,  XIV,  173. 

RILLE:  Zwei  Bruder  mit  Albinismus  Totalis  Congenitus,  Miinch.  med.  Wchnschr., 
1908,  LV,  592. 

SCHULTZ,  W. :  Kaltepigmentierung  von  Albinohaar  und  -auge  im  Regensglase. 
Genetische  Physiologic,  Pfliiger's  Arch.  f.  d.  ges.  Physiol.,  1929,  CCXXI, 
386. 

SHAAD,  D.  J.:    Dark  adaptation  in  albinotic  eye.  Arch.  Ophth.,  1933,  IX,  179. 

SQUIRE,  A.  J.  B.:    An  atypical  albino,  Lancet,  1895,  I,  282. 

STIVEN,  H.  E.  S.:    A  Sudanese  albino,  Lancet,  1923,  I,  648. 

WAKEFIELD,  E.  G.  and  DELLIXGER,  S.  C:  Identical  albino  twins  of  negro 
parents,  Ann.  Int.  Med.,  1936,  IX,  1149. 

Sept.  I,  1937 


Vol.  I.  937 


CHAPTER  XIII 

ADOLESCENCE 

By  WILLIAM  PALMER  LUCAS 

Table  of  Contents 

Introduction 521 

Growth  Changes  of  the  Adolescent  Period 522 

General   Body   Growth 522 

Growth  of  the  Heart 523 

Growth  of  the  Lungs 524 

Growth  of  the  Brain 524 

Growth  of  the  Larynx 525 

Growth  of  the  Reproductive  Organs .525 

Physiological  Development  and  Changes 525 

Psychological  Development  and  Changes 526 

The  Defects  of  Adolescence 528 

The  Diseases  of  Adolescence 53i 

Treatment  of  Various  Conditions 535 

Certain  Problems  of  Adolescence 535 

The  Teaching  of  Social  Hygiene 537 

Introduction 

The  adolescent  period  represents  the  second  most  rapid  period  of 
growth  in  a  child's  development.  From  the  anatomical  standpoint,  this 
period  does  not  represent  as  rapid  a  growth  as  the  period  of  infancy,  but 
the  significance  of  its  anatomical,  psychological,  and  physiological  devel- 
opment is  greater  than  at  any  other  period  of  growth.  During  this  period 
certain  finalities  along  the  lines  referred  to  are  definitely  established.  At 
the  same  time  the  period  covered  by  adolescence  is  a  "  fluid  "  one ;  the 
finalities  established  when  adult  life  is  reached  have  passed  through 
various  phases  of  development.  The  very  character  of  this  period  of 
adolescence,  therefore,  demands  a  most  careful  analysis  of  the  different 
stages  of  the  development.  But  more  than  that,  it  demands  also  of  the 
study  of  medicine  a  more  "  fluid  "  attitude  toward  this  field  and  a  wider 
knowledge  of  the  social  experience  through  which  a  child  passes  during 
the  stage  of  development.  A  sympathetic  appreciation  of  the  child's 
world  is  absolutely  necessary  if  the  changing  phases  of  this  period  are 
to  be  intelligently  related  to  the  whole  field  of  medicine.    The  study  of 

521 


522  ADOLESCENCE 

the  adolescent  period  is  therefore  a  study  of  constant  changes,  and  the 
relation  of  these  changes  to  each  other  and  to  the  whole  development, 
is  the  effort  attempted  here. 

Growth  Changes  of  the  Adolescent  Period 
General  Body  Growth 

The  accepted  opinions  on  this  subject  recognize  the  so-called  time 
element  which  must  be  considered ;  i.e.  the  fact  that  growth,  as  it  takes 
place  at  any  given  period,  is  a  variable.  Growth  proceeds  in  curves  rather 
than  in  straight  lines  during  any  period,  and  the  very  waves  of  the 
curves  vary  in  height  and  width.  Thus  during  the  period  of  adolescence 
growth  must  be  considered  from  the  particular  part  under  observation 
rather  than  from  the  general  standpoint.  Space  permits  of  discussing 
only  the  main  points  of  growth  during  this  period.  The  size  of  the 
skull  remains  practically  the  same,  any  slight  change  being  relative  to 
the  growth  of  other  parts  of  the  bony  structure,  such  as  the  increased 
lengthening  of  the  face  by  the  growth  of  the  jaw  bone. 

A  marked  difference  takes  place  in  the  chest  during  the  adolescent 
period ;  the  growth  takes  place  laterally  and  we  have  increased  width  in 
the  chest  cavities  rather  than  any  marked  increase  in  depth.  The  long 
bones  of  the  body  increase  rapidly  in  growth,  and  here  the  growth  curves 
vary  at  different  times  during  the  period,  and  in  the  two  sexes  differences 
in  the  time  element  have  been  noted.  The  final  attachment  of  the 
epiphyses  that  have  not  already  ossified  takes  place  during  this  period. 
The  final  rounding  out  of  the  muscular  system  is  the  "  normal  "  muscle 
limit  of  this  period.  This  long  bone  and  muscle  development  of  the 
adolescent  period  bears  an  immediate  relation  to  several  of  the  most 
common  characteristics  of  the  so-called  "  awkward  age."  When  the 
bones  grow  more  rapidly  than  the  muscles,  we  often  have  the  "  growing 
pains  "  of  adolescence  as  the  physical  result.  Also  this  rapid  growth  of 
bone  without  the  muscular  development  to  uphold  the  bony  structure 
results  in  poor  posture  for  the  child,  with  far-reaching  results  of  such 
abnormality. 

When  the  muscles  grow  faster  than  the  bones,  the  joints  are  loose  and 
this  often  accounts  for  the  ungainly  habits  of  the  adolescent  child.  The 
clumsiness  noted  in  the  child,  whose  earlier  muscular  skill  had  been 
marked,  is  often  caused  by  the  rapid  growth  of  the  large  muscles  em- 
ployed in  the  finer,  more  detailed  use,  say  of  one's  hands.  Take  the 
emphasis  placed  upon  the  piano  lessons  of  the  small  child.  The  finer 
muscles  are  developed  then — if  this  were  not  so,  they  would  lose  their 
chance  for  development  during  the  adolescent  period,  as  that  period  is 


GROWTH  CHANGES  OF  ADOLESCENT  PERIOD       523 

mainly  devoted  to  the  development  of  the  large  fundamental  muscles. 
The  end  of  the  adolescent  period  has,  in  the  main,  usually  established  the 
final  bony  structures.  Both  the  shoulder  and  pelvic  girdles  in  boys  and 
girls  develop  rapidly  during  the  period.  The  pelvic  development  in  both 
male  and  female  is  the  most  clearly  defined  in  the  adolescent  period,  the 
female  pelvis  becoming  broader  horizontally  than  the  male,  and  parallels 
in  its  development  the  growth  of  the  generative  organs.  The  male  pelvis 
becomes  more  fixed  than  the  female,  as  the  complete  ossification  of  the 
female  pelvis  is  deferred  to  a  later  period.  This  is  a  most  important 
point  in  the  problems  of  attending  maternity. 

Finally,  within  certain  broad  limits,  the  appearance  and  development 
of  metacarpal  bones  is  of  value  in  estimating  the  different  periods  of 
development.  This  metacarpal  development,  however,  cannot  be  used  as 
an  absolute  gauge,  either  physiologically  or  chronologically,  for  any  defi- 
nite age.  The  rapid  increase  in  height,  which  includes  not  only  the  more 
rapid  development  of  the  extremities  but  also  the  slower  but  gradual 
lengthening  of  the  trunk,  is  the  essential  index  of  development  during 
the  adolescent  period.  The  child  should  be  taught  to  be  proud  of  his 
height  and  not  allowed  to  develop  bad  posture,  which  only  increases  his 
awkwardness  and  often  leads  to  permanent  deformities,  such  as  scoliosis. 

Growth  of  the  Heart 

The  heart  develops  rapidly  during  the  period  of  adolescence.  The 
increase  in  size  and  strength  is  marked,  the  volume  of  the  heart  increas- 
ing from  160  to  225  cubic  centimeters.  This  is  not  only  a  growth  in  the 
size  of  the  contractile  fibers  but  also  in  the  number  of  fibers.  Before 
puberty,  the  blood  vessels  are  large  and  the  heart  small.  With  the 
increase  in  the  size  of  the  heart  this  relation  changes.  The  more  rapid 
this  adjustment  between  heart  and  arteries  the  sooner  and  more  complete 
is  the  adolescent  development.  The  general  tendency  during  this  period 
is  for  the  rate  of  the  heart  to  diminish  and  the  strength  of  the  individual 
contraction  of  the  heart  to  increase,  but  there  are  many  unaccountable 
variations  in  the  heart  rate  and  the  forces  of  the  cardiac  impulse.  These 
variations  cause  at  times  pronounced  palpitation,  at  other  times  marked 
slowing  down  of  the  heart  rate.  This  often  causes  alarm  in  the  child, 
awakening,  so  to  speak,  a  consciousness  of  his  heart  which  he  does  not 
understand.  These  symptoms  are  very  disquieting  and  often  recur 
without  an  apparent  cause.  It  is  probably  more  exaggerated  on  over- 
exertion, such  as  muscle  or  nervous  fatigue.  This  alarm  should  be  sym- 
pathetically dealt  with,  by  a  simple  explanation  of  this  growth  to  the 
child,  and  a  carefully  planned  regimen  which  avoids  the  state  of  over- 
fatigue of  any  kind.     The  disproportion  between  the  general  develop- 


524  ADOLESCENCE 

nient  and  the  development  of  the  heart,  which  often  accounts  for  these 
symptoms,  can  be  demonstrated  not  only  by  physical  examination  but 
most  graphically  by  radiography. 

Growth  of  the  Lungs 

The  vital  capacity  increases  with  the  development  of  the  chest.  This 
development,  as  in  the  development  of  the  heart,  proceeds  in  curves 
rather  than  straight  lines,  and  nothing  affects  its  development  more  than 
proper  breathing  and  correct  posture.  There  has  been  a  great  deal  said 
about  this  being  the  period  of  marked  change  in  the  breathing  of  the 
sexes;  the  boy  maintains  the  more  normal  and  abdominal  breathing,  the 
girl  develops  thoracic  breathing.  This  is  not  a  true  sex  difference,  but  is 
artificial  and  due  to  the  radical  change  in  dress  between  the  sexes,  as  has 
been  clearly  demonstrated  by  Mosher  (^).  During  the  adolescent  period, 
tuberculous  affections  of  early  childhood  are  likely  to  become  active 
processes.  The  early  infection  of  the  bronchial  glands  extends  to  the 
lungs  during  this  period  of  the  direction  of  all  surplus  energy  to 
growth.  Hygiene  and  careful  supervision  of  those  who  have  had  gland 
infection  in  earlier  childhood  is  most  important  at  this  time  to  prevent 
this  pulmonary  extension.  Excessive  fatigue  and  acute  infections  are 
most  important  to  avoid. 

Growth  of  the  Brain 

The  adolescent  period  is  the  most  important  one  in  the  differentiation 
of  the  brain.  At  this  time  there  are  more  active  cells.  The  size  of  the 
brain  and  weight  of  the  brain  have  reached  their  maximum  in  the  pre- 
adolescent  period,  but  adolescence  marks  the  intensification  of  the  dif- 
ferentiation of  the  fibers  which  represent  the  higher  intellectual  powers. 
The  nervous  system  gives  a  clear  illustration  of  regular  and  orderly 
growth.  The  higher  centers  depend  on  their  development  upon  the 
growth  of  the  lower  centers.  This  development  of  the  higher  centers 
progresses  rapidly  during  the  adolescent  period  connecting  the  sensory 
and  motor  areas.  This  growth  of  association  fibers  is  apparently  stimu- 
lated by  the  appearance  of  our  higher  intellectual  powers.  During  the 
adolescent  period  there  is  undoubtedly  an  increased  stimulation  in  new 
centers.  These  centers  are  not  limited  to  sensory  or  motor  aspects,  but 
undoubtedly  have  to  do  with  the  higher  centers  of  volition  and  will. 
The  inter-reaction  of  different  centers  causes  development  and  growth  of 
other  centers,  so  that  we  have  a  number  of  different  periods  of  growth, 
as  it  is  true  that  certain  fibers  become  medullated  far  earlier  than  others. 
During  the  adolescent  period  new  interests  and  cravings  appear  and  un- 
doubtedly are  related  to  the  maturing  of  certain  association  centers, 


PHYSIOLOGICAL  DEVELOPMENT  AND  CHANGES     525 

Growth  of  the  Larynx 

The  larynx  grows  rapidly  at  adolescence  with  quite  a  marked  sex 
difference,  the  male  growing  larger  than  the  female.  All  the  cartilages 
are  enlarged  and  the  thyroid  cartilage  in  the  male  becomes  quite  promi- 
nent and  the  glottis  nearly  doubles  in  length.  This  development  of  the 
larynx  includes  the  development  of  the  vocal  cords,  which  lengthen  and 
thicken ;  accounting  thus  for  the  change  in  voice,  especially  in  boys,  during 
this  period.  A  boy's  voice  commonly  breaks  at  this  time  and  often 
becomes  a  full  octave  lower. 

Growth  of  the  Reproductive  Organs 

The  first  indication  of  the  growth  of  these  organs  is  found  in  the 
development  of  secondary  sexual  characteristics.  Hair  begins  to  appear 
in  the  pubic  regions  and  the  armpits  of  both  boys  and  girls.  In  boys, 
there  is  a  more  marked  increase  in  hair  on  the  face,  chest,  abdomen,  as 
well  as  all  over  the  body.  In  girls,  there  is  a  marked  rounding  out  of 
the  hips  and  the  development  of  the  breasts.  The  reproductive  organs, 
themselves,  begin  to  develop  in  size.  The  penis  and  testes  of  boys  show 
marked  change  in  size  as  do  the  uterus  and  vagina  in  girls. 

Physiological  Development  and  Changes 

The  foregoing  general  discussion  of  growth  leads  naturally  to  the 
consideration  of  the  effect  of  growth  upon  the  function  of  the  organs  of 
the  body  and  the  resultant  physiological  changes.  At  the  time  of  the 
beginning  of  the  development  of  the  sex  organs,  we  have  the  first  funda- 
mental appearance  of  the  physiological  activity  of  the  gonad  system  or 
sex  glands.  This  development  is  one  of  the  most  complex  processes 
taking  place  in  the  body,  because  upon  it  is  based  the  differentiation  of 
the  sexes  and  the  power  of  normal  reproduction  in  both.  The  develop- 
ment of  the  gonad  system  is  intimately  associated  with  the  normal  func- 
tioning of  other  internal  glands.  Any  disturbance  in  the  pituitary  glands 
usually  affects  the  normal  development  of  the  sex  glands.  Changes  in 
the  adrenal  and  thyroid  glands  also  affect  the  normal  functioning  of  the 
reproductive  glands. 

Closely  paralleling  the  development  of  the  internal  secretions  come 
the  external  signs  of  sex  functioning,  which  at  the  beginning  often  cause 
great  mental  and  nervous  suffering.  In  boys,  the  appearance  of  noc- 
turnal seminal  emission  is  not  at  all  regular,  recurring  at  first  at  infre- 
quent intervals  and  normally  at  the  height  of  puberty,  not  oftener  than 
once  in  ten  days  or  two  weeks.    This  emission  is  often  accompanied  by 


526  ADOLESCENCE 

dreams.  The  semen  is  composed  of  a  thick  gelatinous  secretion  contain- 
ing many  active  spermatozoa.  Menstruation  in  girls  occurs  with  greater 
regularity,  the  normal  periodicity  being  twenty-four  days.  The  duration 
of  the  flow  varies  in  normal  limit  from  two  to  five  days.  Under  condi- 
tions of  poor  hygiene,  both  physical  and  mental,  the  menstrual  function 
is  very  often  disturbed,  and  this  disturbance  often  produces  the  common 
pathological  condition  of  amenorrhea  and  dysmenorrhea.  In  a  few  in- 
stances these  conditions  are  undoubtedly  due  to  derangement  in  the 
internal  gland  secretion,  but  by  far  the  majority  are  due  to  improper 
hygiene. 

Menstruation  is  undoubtedly  influenced  by  the  internal  secretion  of  the 
ovaries.  The  thymus,  the  posterior  lobe  of  the  pituitary  and  the  thyroid 
are  also  supposed  to  play  a  part  in  menstruation.  There  is  undoubtedly  a 
relation  between  the  mammary  glands,  which  become  enlarged  immedi- 
ately before  the  menstrual  period.  During  menstruation  the  uterus  is 
markedly  hyperemic  and  the  flow  of  blood  is  the  result  of  this  normal 
condition.  This  blood  contains  varying  numbers  of  endothelial  cells  from 
the  uterus  and  epithelial  cells  from  the  vaginal  tract.  Changes  in  the 
skin  occur  constantly  during  this  period.  In  girls  the  pigmentation  is 
most  pronounced  in  the  areola  of  the  nipple.  The  decided  change  in  the 
complexion  of  both  boys  and  girls  is  marked  at  this  time.  The  sebaceous 
glands  enlarge  and  become  more  easily  infected  and  are  responsible  for 
the  frequency  of  acne  during  adolescence.  Blackheads  are  very  common 
during  this  period,  caused  by  the  growth  of  the  sebaceous  glands  and  the 
pigmentation.  Connected  with  the  skin  changes  are  the  presence  of 
characteristic  body  odors,  which  are  more  pronounced  in  girls  during  the 
menstrual  period.  Perspiration  increases  in  both  boys  and  girls.  The 
activity  of  the  salivary  glands  increases  during  this  period.  The  spitting 
contests  of  the  small  boys  are  familiar  to  all.  During  the  adolescent 
period  the  physiological  changes  in  the  organs  of  sense  are  on  the  whole 
slight.  Sight  and  hearing  are  not  affected.  Smell  and  taste  are  slightly 
accentuated.  The  craving  for  sweets  is  a  common  symptom.  The 
tactile  sense  may  be  increased  or  diminished. 

Psychological  Development  and  Changes 

Adolescence  is  the  period  of  great  awakening  and  change  both  men- 
tally and  morally.  The  child  passes  from  the  "  gang  "  stage  to  the  stage 
of  a  larger  group,  society  in  general.  He  becomes  more  conscious  of 
himself  as  an  individual  and  that  consciousness  demands  his  own  relation 
to  others  as  well  as  to  his  environment.  The  desire  to  count  as  one  and 
a  part  of  the  whole  slowly  overshadows  the  former  contentment  in  act- 


PSYCHOLOGICAL  DEVELOPMENT  AND  CHANGES  527 

ing  merely  in  the  "  gang  "  spirit.  This  change  cannot  be  tabulated.  It  is 
even  more  fluid  than  the  physical  change.  The  only  wise  method  is  the 
constant  study  of  each  phase  as  it  presents  itself.  For  the  first  time  con- 
sciousness of  dress  appears  in  both  boys  and  girls.  Anything  that  seems 
to  call  attention  to  oneself  is  the  most  sought  after,  a  tie  of  gay  colors, 
a  bizarre  ornament  worn  at  an  unusual  angle,  all  the  many  ways  in  which 
the  individual  may  be  marked  by  his  kind.  On  the  other  hand,  there 
may  be  periods  of  absolute  personal  neglect,  arising  from  the  same  indi- 
vidual awakening  and  marking  a  stronger  development :  "  to  be  in  a 
group  yet  not  of  it,  is  an  old  standard  of  moral  strength." 

The  actual  mental  caliber  of  boys  and  girls  at  this  period  may  be 
equally  bafiling.  Sometimes  it  is  marked  by  precociousness  in  their 
mental  processes.  They  may  show  a  great  power  of  assimilation  in  a 
subject  that  interests  them ;  again  they  may  be  absolutely  indifferent  to 
any  mental  achievement  and  for  the  time  being  have  lost  interest  in  any- 
thing and  everything  that  has  to  do  with  their  mental  development. 
These  mental  states  are  usually  closely  associated  with  their  physical 
development.  When  their  physical  development  seems  to  be  progressing 
most  rapidly,  the  mental  activity  seems  to  be  at  a  standstill.  Often  the 
strength  of  the  child  is  entirely  absorbed  by  the  physical  growth.  At 
other  times  when  the  physical  development  progresses  slowly  the  mental 
activity  may  develop  very  rapidly.  Again  there  may  be  a  rapid  and  even 
development  of  both  the  physical  and  mental  powers,  or  there  may  be  a 
slow  and  even  development  of  both  the  physical  and  mental  powers  and, 
lastly,  that  most  baffling  of  all  phases,  when  both  the  mental  and  physical 
developments  seem  to  be  marking  time.  These  unevennesses  are  marked, 
mentally  and  emotionally,  in  various  ways. 

Sex  attraction  now  manifests  itself  and  often  begins  with  a  strong 
devotion  between  members  of  the  same  sex.  Boys  have  their  boy  heroes 
of  their  own  age  and  older.  Girls  are  more  apt  to  be  attracted  by  older 
women,  especially  their  teachers.  Adolescence  is  often  marked  by  vivid 
religious  emotions  and  aspirations,  utterly  unfounded  likes  and  dislikes, 
periods  of  uncontrolled  temper,  periods  of  equally  unreasonable  spells  of 
contrition,  periods  of  great  excitement  and  high  spirits,  and  again  periods 
of  deep  depression.  Taste  in  food  as  well  as  dress  suffers  from  the 
uneven  developments  of  this  period.  All  these  manifestations  differ  in 
degree  and  intensity  throughout  the  whole  period  of  adolescence  and  there 
seems  to  be  no  consistency  in  sequence  in  any  two  individuals.  There- 
fore the  understanding  and  relative  importance  of  these  changes  neces- 
sitates a  careful  study  of  each  child.  The  period  is  marked  by  greater 
variations  within  the  normal  than  any  other  period  of  human  develop- 
ment. 


528  ADOLESCENCE 

In  spite  of  all  this  ebb  and  flow,  this  varied  expression  of  adolescent 
contrasts  and  inconsistencies  in  the  relationship  between  the  mental  and 
physical  development,  certain  definite  mental  finalities  are  steadily  being 
approached.  At  the  end  of  adolescence,  the  power  to  reason  has  become 
stabilized  and  ready  for  its  mature  development.  The  will  power,  most 
unstable  during  adolescence,  if  normal  in  development,  becomes  more 
fixed  and  ready  to  build  upon.  The  character  development  during 
adolescence  is  but  a  continuation  and  molding,  so  to  speak,  of  processes 
begun  in  the  very  earliest  adaptation  of  a  child  to  its  environment. 
During  the  adolescent  period,  the  same  "  fluid  "  conditions  exist  in  the 
moral  adjustments  as  in  the  physical  and  mental  development.  We  often 
find  that  a  child  during  this  period  of  adolescent  variation  develops  weak 
or  vicious  traits  which,  unless  properly  and  sympathetically  guided,  might 
become  stabilized.  If  so  guided,  the  child,  when  adolescence  is  completed, 
emerges  with  the  moral  finalities  that  were  established  long  before  the 
adolescent  period  began.  At  the  same  time  the  child  entering  the 
adolescent  period  with  the  wrong  moral  concepts  has  in  the  very  nature 
of  the  period  itself,  its  instability  and  variation,  a  new  chance  to  develop 
the  right  moral  valuation.  Such  moral  development  during  adolescence 
is  closely  related  to  the  development  'of  the  mental  powers,  such  as  the 
reason  and  the  will.  For  reasons  such  as  these,  the  strongest  emphasis 
must  be  placed  upon  the  care  and  guidance  of  children  through  this 
period,  as  it  is  the  last  opportunity  for  the  molding  of  character.  While 
not  as  important  as  the  earlier  stage,  still  it  is  the  last  opportunity  for 
permanently  affecting  character  formation.  Radical  changes  of  char- 
acter after  the  completion  of  adolescence  are  rare  and  are  usually  the 
result  of  great  or  disturbing  elements  in  life,  such  as  rehgious  conversion 
or  exposure  to  tremendous  emotional  experiences,  great  joy,  fear  or 
tragedy,  as  the  war  has  demonstrated. 

The  Defects  of  Adolescence 

Such  a  period,  marked  deeply  as  it  is  by  constant  change,  growth 
and  development  along  physical,  mental  and  psychical  lines,  is  naturally 
marked  by  defects  of  great  gravity.  These  defects  naturally  fall  into  two 
groups — the  defects  of  heredity,  and  acquired  defects.  Defects  of 
heredity  again  fall  into  the  two  main  groups  of  those  inheriting  mental 
defects  and  those  inheriting  moral  defects.  The  mental  defects  which 
appear  first  during  adolescence  are  mainly  the  moron  group.  These  indi- 
viduals form  a  great  part  of  our  adolescent  juvenile  ofifenders,  especially 
among  girls.  The  increased  instability  of  the  period,  plus  the  weak  men- 
tality, minus  a  good  environment,  leads  usually  to  the  breaking  of  some 


THE  DEFECTS  OF  ADOLESCENCE    '  529 

social  law  in  these  cases.  In  girls,  it  is  more  often  a  sex  offense,  in  which 
case  they  are  more  unmoral  than  immoral,  having  been  used  by  normal 
people  who  should  be  the  real  offenders  against  the  law.  As  to  boys,  of 
the  moron  group,  we  find  them  in  the  same  status,  being  used  by  brighter 
more  normal  individuals  as  tools,  and  the  common  offenses  are  larceny, 
truancy  and  depredations  of  various  sorts.  The  moron,  it  must  be 
remembered,  is  the  individual  whose  maximum  intelligence  equals  the 
normal  intelligence  of  twelve  years. 

During  the  unstable  period  of  adolescence  the  moron  can  be  trained 
into  certain  habits  of  life  and  work  that  will  make  him  often  economically 
independent.  This  can  be  accomplished  by  vocational  training  along 
manual  lines  under  careful  supervision.  Nor  does  this  mean  constant 
institutional  care.  By  special  classes  in  the  public  schools,  combined  with 
constant  careful  follow-up  work  in  the  homes,  many  of  these  individuals 
can  be  kept  out  of  trouble  and  can  constructively  use  the  limited  abilities 
they  possess.  This  type  of  care  is  possible  but  it  is  only  possible  with 
community  understanding  and  cooperation  between  school,  family  and 
the  follow-up  workers.  The  majority  of  morons  who  go  wrong  during 
the  adolescent  period  do  so  from  a  lack  of  this  cooperative  effort  and  a 
lack  of  understanding  of  a  child's  limitations.  The  stress  and  storm  of 
the  adolescent  period  is  much  harder  on  the  moron  group  than  upon  the 
normal  child  because  they  lack  the  development  of  the  higher  mental 
traits,  reason,  will  power  and  judgment,  which  come  to  the  normal  child 
during  that  period.  The  moron's  maximum  intelligence  of  twelve  years 
may  not  be  reached  until  the  later  years  of  adolescence,  which  makes  the 
problem  very  much  more  difficult.  The  adolescent  changes  have  to  be 
met  without  the  stabilizing  effect  of  mental  development.  On  the  other 
hand,  many  of  the  moron  group  do  not  seem  to  experience  the  stress  of 
the  adolescent  period,  but  on  account  of  their  lack  of  mental  development 
are  just  as  easily  led  astray.  Many  of  these  children  cannot  be  cared 
for  successfully  in  communities  where  general  understanding  and 
cooperation  are  lacking,  and  as  such  communities  are  as  yet  in  the  vast 
majority  in  the  world,  the  institution  becomes  a  necessity  for  the  care  of 
the  moron.  The  type  of  institution,  however,  should  be  one  which 
embodies  all  that  outside  care  might,  in  special  instances,  accomplish. 
The  old  idea  of  merely  shutting  such  children  away  from  the  world  has 
passed  forever  and  the  new  institution  has,  as  its  goal,  the  final  placing 
of  the  moron  in  society  again,  so  stabilized  and  trained  by  habit  and 
education  fitted  to  his  powers  that  he  can  be  a  self-supporting  and  self- 
respecting  member  of  the  group.  This  would  always  necessitate  a  certain 
amount  of  intelligent  supervision,  varying  with  the  demands  required  of 
the  individual  and  the  changing  environment.    Friendly  advice  from  the 


530  ADOLESCENCE 

modern  trained  medical  social  worker  should  always  be  available  to  this 
group  in  order  that  the  individual  may  be  able  to  make  his  adjustments 
to  new  demands  without  a  loss  of  the  training  he  has  had. 

Another  group  which  suffers  keenly  during  the  adolescent  period  is 
that  composed  of  children  whose  mentality  is  not  below  normal  but  who 
suffer  from  lack  of  moral  stamina.  These  children  are  much  more  diffi- 
cult to  detect  because  their  intelligence  is  normal.  They  show  usually  a 
total  lack  of  the  social  sense,  no  perception  of  right  and  wrong,  and  from 
this  group  come  many  of  our  criminal  class  and  the  worst  offenders 
against  sex  laws.  The  understanding  and  management  of  this  group  is 
much  more  difficult  than  that  of  the  moron,  and  the  success  of  training 
and  supervision  is  markedly  less  because  their  intelligence  gives  them  an 
advantage.  If,  at  early  periods,  some  decided  bent  or  aptitude  can  be 
discovered  and  the  training  and  supervision  related  to  it  most  carefully 
and  intelligently  applied,  the  chances  of  success  are  much  greater. 

A  third  group  of  defectives  which  appears  usually  during  the  adoles- 
cent period  is  that  of  so-called  constitutional  psychopaths.  These  indi- 
viduals are  of  varying  types,  their  principal  defect  being  their  inability  to 
adapt  themselves  to  the  normal  environment.  Many  in  this  class  have 
what  is  recognized  as  a  hereditary  nervous  background  (diathesis)  which 
shows  itself  in  the  constant  impulsive  basis  from  which  they  act.  We 
find  in  this  group  all  our  cranks,  kleptomaniacs,  pyromaniacs,  agitators, 
and  all  the  impulsive  types  that  make  up  our  grave  social  problems.  The 
keen  intelligence  which  often  marks  these  impulsive  psychopaths  makes 
them  most  difficult  to  treat  with  the  intelligence  they  demand.  During 
adolescence  these  types  first  reveal  themselves,  and  that  period  should  be 
most  carefully  studied  by  students  of  medicine.  In  the  past  there  has 
been  little  appreciation  by  the  medical  profession  of  the  importance  of 
such  manifestations  during  adolescence.  But  of  late,  such  intensive 
studies  as  have  been  carried  on  by  Healy  (")  and  by  the  best  modern 
psychopathic  hospitals,  juvenile  clinics  and  juvenile  courts,  have  brought 
to  the  attention  of  the  medical  profession  a  vast  amount  of  material  that 
shows  the  importance  of  the  understanding  of  the  heredity  and  environ- 
ment of  these  cases. 

The  fundamental  aspect  to  be  stressed  in  handling  these  cases  is  to 
make  every  attempt  during  the  plastic  period  of  adolescence  to  force 
upon  these  individuals  the  realization  of  their  own  condition.  In  this 
is  a  surer  hope  of  solution  for  them.  Psychoanalysis,  if  used  at  all, 
should  be  used  not  so  much  in  the  Freudian  sense  of  establishing  all  lines 
of  relation  of  abnormal  traits  to  sexual  development,  as  in  the  analysis 
of  the  individual's  own  life  so  that  he  will  understand  his  own  weak- 
nesses and  handicaps.     In  modern  social  psychology  we  have  a  better 


DISEASES  OF  ADOLESCENCE  531 

means  of  stimulating  the  child  to  an  appreciation  of  the  development  of 
his  instincts  and  so  helping  him  to  gain  a  more  stable  control  over  his 
defective  impulsive  bases. 

Another  group  of  defectives  are  those  suffering  from  language  and 
speech  defects,  which  may  or  may  not  appear  before  adolescence,  but 
which  do  often  appear  and  usually  meet  medical  attention  first  during 
this  period.  Children  with  these  defects  are  often  normal  in  every  other 
respect.  These  defects  may  be  permanent  or  temporary,  and  the  im- 
portance of  understanding  them  is  in  order  to  be  able  to  classify  them, 
so  that  the  training  of  these  children  may  proceed  along  the  lines  in  which 
they  are  normal,  and  in  this  way  to  diminish  their  handicap  as  much  as 
possible. 

Other  types  are  those  defective  in  number  work.  This  often  causes 
a  classification  of  these  children  as  feeble-minded  when  the  defect  is 
limited  to  this  one  faculty.  Stammering  and  similar  speech  defects, 
which  appear  during  the  adolescent  period  in  the  nervous  or  timid  child, 
have  a  definite  neuromuscular  and  mental  or  psychological  basis.  These 
conditions  may  be  begun  through  imitation;  a  sensitive  child  often 
acquires  an  actual  speech  defect  from  contact  with  another  suffering  from 
such  a  defect.  Such  defects  may  also  be  acquired  after  a  definite  fright 
or  shock  of  any  kind  to  the  nervous  system.  Of  course,  this  acquisition 
of  such  defects  may  appear  at  any  age,  but  before  the  completion  of 
adolescence  they  must  be  handled,  if  possible,  as  delay  in  treatment  in- 
creases the  chance  of  permanency.  The  treatment  should  be  carried  out 
by  one  acquainted  with  the  psychology  of  childhood  as  well  as  the 
mechanics  of  voice  production  and  control.  Many  of  these  speech  and 
language  defects  are  hereditary,  many  are  acquired,  and  some  have  the 
double  basis. 

Diseases  of  Adolescence 

This  period  is  marked  by  the  development  of  definite  psychoses, 
mainly  those  of  mania  and  melancholia.  These  states  often  have  an 
hereditary  basis,  but  are  usually  brought  into  evidence  by  the  awakening 
of  the  sexual  functions.  The  state  of  mania  is  characterized  by  periods 
of  intense  excitement,  uncontrolled  temper,  followed  by  periods  of  great 
fatigue.  Sometimes  intense  jealousy,  great  selfishness,  sharp  depression 
are  manifested.  The  state  of  melancholia  is  expressed  by  constant  de- 
pression maintained  sometimes  over  long  periods.  While  there  are  inter- 
vals of  normality  and  cheerfulness,  depression  is  the  more  constant 
symptom. 

The  treatment  of  these  states  requires  as  early  a  recognition  as  pos- 
sible and  a  careful  analysis  of  the  causes,  either  real  or  imaginary,  that 


532  ADOLESCENCE 

have  brought  on  these  states.  The  removal  of  the  causes  and  the  placing 
of  the  child  in  the  best  possible  environment  which  will  prevent  a  recur- 
rence of  the  cause,  is  the  best  line  of  treatment  to  be  followed.  In  the 
more  severe  cases  institutional  care  is  necessary,  but  the  outcome  of  these 
cases  is  not  good  because  they  often  become  chronic  or  fall  into  such  bad 
nutritional  condition  that  they  often  die  of  some  intercurrent  disease. 
The  adjustment  of  these  cases  to  everyday  life  is  one  of  the  most  hopeful 
fields  of  modern  psychiatry.  Careful  study  of  the  individual  case  with 
the  necessary  change  of  environment  and  the  personal  follow-up  work  of 
a  trained  psychiatrist  and  social  worker  bids  fair  to  be  the  best  solution 
possible  for  these  cases. 

A  common  mental  condition  of  adolescence  is  dementia  praecox.  On 
account  of  the  stress  of  rapid  change  of  this  period,  dementia  praecox 
with  its  gradual  decay  of  mental  faculties  is  very  likely  to  appear  in  the 
early  and  confusional  states.  At  that  stage  it  is  often  difficult  to  dif- 
ferentiate the  state  from  an  exaggerated  adolescent  condition  of  insta- 
bility which  corrects  itself.  In  the  most  common  type  of  dementia 
praecox,  the  hebephrenic  type,  are  found  states  of  increased  excitement 
alternating  with  foolish  laughter  and  silly  speech,  an  exaggerated  impulse 
to  be  doing  something  which  is  only  evidenced  by  perfectly  aimless  actions 
which  accomplish  nothing.  These  conditions  may  persist  for  a  long  time 
without  any  evident  increase  in  the  mental  decay,  but  in  general  these 
states  terminate  in  extreme  mental  weakness  followed  by  the  complete 
destruction  of  the  mind.  Other  forms  of  dementia  praecox  may  begin  at 
puberty,  such  as  the  catatonic  form  in  which  states  of  depression  are 
followed  by  alternating  periods  of  stupor  and  excitement  shown  by  varied 
motor  spasms  or  retardations.  Paralytic  dementia  also  has  its  beginnings 
frequently  at  the  period  of  adolescence.  All  these  states  when  actively 
manifested  are  best  handled  in  an  institution. 

Syphilis  is  the  underlying  cause  of  many  of  the  mental  deteriorations 
during  the  adolescent  period.  Hereditary  syphilis  is  sometimes  retarded, 
and  without  having  shown  any  previous  manifestations,  either  in  the 
physical  or  mental  development  of  the  child,  develops  very  rapidly  during 
puberty.  Especially  is  this  true  at  the  time  of  the  development  of  the 
sexual  functions  and  manifests  itself  by  rapid  mental  deterioration  or  by 
the  development  of  juvenile  tabes.  Active  treatment  with  mercury  and 
salvarsan  or  neosalvarsan  begun  early  may  be  able  to  check  the  condition, 
but  these  conditions  more  often  continue  to  rapid  disintegration  both 
mentally  and  physically.  Such  cases  usually  die  of  some  intercurrent 
infection. 

Because  of  the  fundamental  change  in  the  brain  and  central  nervous 
system   and  marked  physiological   changes,   epilepsy   reaches   its  most 


DISEASES  OF  ADOLESCENCE  533 

marked  development  during  adolescence.  Instead  of  the  hoped  for  cessa- 
tion of  symptoms,  they  are  usually  exaggerated  during  this  period. 
When  chorea  appears  first  at  adolescence,  it  is  marked  by  greater  severity 
and  longer  periods  of  duration.  The  characteristic  involuntary  move- 
ments are  usually  accompanied  by  irritability,  absent-mindedness  and 
slight  mental  weakness. 

Changes  in  the  composition  of  the  blood  during  adolescence  often 
take  place,  especially  the  anemias  which  are  marked  by  pallor  and  great 
languor.  In  boys,  this  usually  takes  the  form  of  simple  secondary  anemia, 
due  to  the  effects  of  malnutrition  or  previous  infection.  During  adoles- 
cence this  secondary  anemia  may  become  quite  pronounced  on  account 
of  the  increased  demands  of  growth  and  the  disturbances  caused  by  the 
development  of  internal  glandular  secretions  on  the  lymphatic  system. 
In  girls  these  anemias  often  take  the  exaggerated  form  of  chlorosis,  in 
which  there  is  a  definite  disturbance  of  lymph  formation.  The  red  cells 
are  not  able  to  carry  their  normal  proportion  of  hemoglobin  so  that  the 
characteristic  finding  of  this  condition  is  a  very  marked  reduction  in  the 
hemoglobin  without  a  corresponding  reduction  in  the  red  cells.  In 
severe  cases,  poikilocytes  and  normoblasts  make  their  appearance.  Con- 
nected with  these  blood  findings  are  marked  lassitude  and  fatigue  which 
chlorotic  girls  suffer  from,  and  also  distinct  nervous  phenomena  such 
as  headache,  vertigo,  insomnia,  and  general  nervous  instability.  These 
conditions  are  often  accompanied  by  hemic  murmurs  of  the  heart  and 
change  in  the  blood  pressure.  Their  treatment  requires  careful  regula- 
tion of  diet  and  regime  based  upon  a  study  of  their  previous  condition, 
making  sure  that  the  cause  is  neither  syphilis  nor  tuberculosis.  Iron  in 
most  instances  has  a  very  definite  effect  upon  these  anemias. 

The  endocrine  glands  exert  a  powerful  influence  upon  adolescent 
development  of  both  girls  and  boys,  not  only  on  the  development  of  the 
sex  organs  and  functions  but  also  upon  the  secondary  sexual  character- 
istics. The  functional  activity  of  the  sex  organs  depends  upon  the  har- 
monious action  of  the  endocrine  system,  upon  the  efficient  and  normal 
action  of  this  system.  It  is  not  sufficient  to  have  merely  the  sex  glands 
develop.  The  development  of  the  sex  glands  is  so  intimately  connected 
with  the  development  of  the  thyroid  and  pituitary  glands  that  the  two 
must  progress  in  parallel  lines.  We  know  that  the  thymus  gland  begins 
to  disappear  about  the  time  of  puberty.  Whether  this  disappearance  of 
the  internal  secretion  of  the  thymus  causes  the  beginning  of  the  develop- 
ment of  the  gonad  system  with  its  internal  secretion,  or  whether  the 
appearance  at  this  time  of  the  internal  secretion  of  the  gonads  causes  the 
disappearance  of  the  thymus  gland,  is  not  known.  The  reaction  is 
probably  mutual.    Any  change  in  the  development  of  the  thyroid  or  the 


534  ADOLESCENCE 

pituitary,  causing  an  insufficiency  of  its  internal  gland  secretion,  retards 
the  development  of  the  generative  organs.  A  tumor  in  the  pituitary  will 
cause  infantilism.  Most  of  the  cases  seen  during  adolescence  of  retarded 
or  abnormal  growth  are  due  to  a  combination  of  defects  in  the  endocrine 
system,  usually  a  polyglandular  one.  The  thyroid  gland  during  the 
adolescent  period  is  very  prone  to  enlarge,  especially  in  girls.  Marine  (') 
in  his  studies,  "  Thyroid  in  School  Children,"  found  it  four  times  as 
often  in  girls  as  in  boys.  This  increased  tendency  to  thyroidism  during 
adolescence  has  a  definite  effect  upon  the  development  of  generative 
organs.  The  period  of  nervous  instability  is  markedly  increased  by  this 
tendency.  It  seems  fair  to  assume  that  the  instability  and  the  varying 
phases  of  great  fatigue  and  excitement  are  caused  by  the  uneven  devel- 
opment of  the  internal  glands  or  the  attempt  to  harmonize  their  activities. 
Marine  (^)  has  shown  that  this  condition  is  more  prevalent  in  certain 
regions,  such  as  that  of  the  Great  Lakes.  The  fact  that  this  condition 
may  be  controlled  by  small  doses  of  iodine  offers  a  simple  method  of 
afifecting  this  important  period  of  development  when  it  is  complicated  by 
thyroidism. 

Disturbance  of  the  suprarenal  glands  has  the  opposite  effect,  that  of 
stimulating  the  gonad  development  and  in  the  cases  of  precocious  puberty 
a  tumor  of  the  suprarenals  is  often  found.  In  other  cases,  there  may  be 
simply  an  overstimulation  from  the  suprarenals  which  causes  the  noted 
precocity.  Each  individual  case  of  disturbed  adolescence,  either  delayed 
or  precocious,  must  receive  careful  study  of  the  endocrine  gland  system 
to  determine  which  glands  are  at  fault.  Some  very  definite  effects  can 
be  obtained  from  appropriate  glandular  treatment,  especially  in  cases 
where  we  can  determine  some  definite  derangement.  Many  cases,  how- 
ever, are  most  baffling,  and  there  is  no  field  in  medicine  related  to  the 
adolescent  period  that  needs  more  intelligent  study  than  this  of  the 
endocrine  system. 

Growth  is  not  a  simple  nor  a  single  process  but  is  a  multiplex  phe- 
nomenon, as  described  by  Robertson  (*)  in  his  discussion  of  the  growth 
factor  found  in  the  anterior  lobe  of  the  pituitary.  He  states  that  "  it 
would  appear  legitimate  to  infer  that,  at  a  late  stage  in  the  third  adoles- 
cent growth  cycle,  the  administration  of  excess  of  pituitary  anterior 
lobe  tissue  leads  to  an  acceleration  of  growth  while,  at  an  earlier  stage 
in  the  development  of  animals,  the  administration  of  anterior  lobe  tissue 
leads  to  retardation  of  the  rate  of  growth."  He  concludes  that  "  it  is 
quite  conceivable  that  pre-adolescent  hypopituitarism  at  a  certain  stage  of 
development  might  yield  effects  in  some  respects  analogous  to  those  of 
late  post-adolescent  hyperpituitarism."  He  was  able  to  produce  such 
effects  with  the  extract,  tethelin,  which  he  obtained  from  the  anterior 


CERTAIN  PROBLEMS  OF  ADOLESCENCE     535 

lobe,  completely  changing  the  growth  cycle  of  adolescence.  Clinically  we 
see  many  cases  which  during  adolescence  undoubtedly  show  some  dis- 
turbance in  the  normal  development  and  secretion  of  the  pituitary  gland, 
causing  a  disturbance  in  the  normal  progress  of  adolescence.  Besides  the 
clear-cut  cases  of  hypo-  or  hyper-pituitarism  we  probably  have  many 
more  cases  in  which  there  is  a  dys-pituitarism  connected  with  disturbances 
in  some  other  gland ;  most  often  in  my  experience  this  is  connected  with 
hypothyroidism. 

Treatment  of  Various  Conditions 

The  treatment  of  these  various  conditions  demands  first  of  all  a  care- 
ful study  of  all  the  changes  of  the  period  of  adolescence,  the  anatomical, 
physiological  and  psychological  developments.  The  anatomical  and 
physiological  disturbances  are  best  handled  by  the  most  intelligent  con- 
sideration of  the  details  of  life.  The  amount  of  recreation  needs  careful 
regulation.  Sleep  and  rest  are  most  important  items.  Adolescence  de- 
mands a  more  nutritive  diet  than  any  other  period  of  life.  The  school 
studies  carried  on  in  this  country  show  that  the  food  and  the  variety  taken 
by  adolescents  far  exceeds  the  demands  of  any  other  period,  amounting  to 
from  four  to  five  thousand  calories  a  day  for  boys.  The  writer's  own 
experience  in  studying  the  "  ravitaillement "  system  in  Belgium  and 
the  north  of  France  emphasized  the  great  ravages  made  in  this  period,  due 
to  diminished  food.  The  period  of  adolescence  stood  out  markedly  as 
one  which  could  not  hold  its  own  on  the  food  ration  of  an  adult.  This 
condition  is  now  known  to  exist  over  all  of  war-ravaged  Europe  and  the 
adolescent  period  has  suffered  most  from  the  stern  restriction  of  diet 
caused  by  the  war.  The  varied  psychological  changes,  which  have  almost 
an  infinite  number  of  combinations  and  aspects,  need  most  sympathetic 
understanding  and  firm,  skilled  handling.  As  already  indicated  more 
than  this,  the  constant  interrelation  of  all  these  changes  must  never  be 
lost  sight  of,  as  most  often  the  study  of  the  whole  gives  the  key  for  the 
particular  problem. 

Certain  Problems  of  Adolescence 

While  all  the  varied  changes  of  adolescence  present  many  problems, 
conduct,  which  is  the  result  of  the  individual's  effort  to  adjust  himself  to 
the  demands  of  his  environment,  during  adolescence  presents  many  of  the 
most  acute  difficulties.  The  mass  of  material  accumulated  bv  the  juvenile 
courts  of  the  country  are  crowded  with  instances  of  mal-adjustment,  of 
bad  conduct  which  results  disastrously  for  the  individual.  These  cases 
represent  in  varying  degrees  the  anatomical,  physiological  and  psycho- 


536  ADOLESCENCE 

logical  defects  of  adolescence.  Masturbation,  which  is  one  of  the  most 
frequent  sexual  acts  indulged  in  by  the  adolescent  boy  and  girl,  is  found 
much  more  frequently  in  these  cases  of  mal-adjustment.  Where  mas- 
turbation is  a  persistent  factor,  it  is  commonly  associated  with  mental  or 
moral  defect. 

Healy  (^)  has  carefully  studied  these  problems  of  individual  conduct 
and  he  urges  the  most  intelligent  study  of  the  cases  accompanied  by  an 
honest  effort  to  adequately  solve  the  problem.  Ordinarily  this  solution 
is  left  to  the  judge  of  the  court.  In  rare  instances  he  has  the  advice  of 
a  trained  psychologist.  In  that  case,  he  may  desire  to  act  in  the  most 
intelligent  manner,  but  the  judge  has  his  limitations.  He  can  do  one  of 
three  things,  place  the  delinquent  child  on  probation,  assign  him  to  an 
institution,  or  drop  the  case.  If  dropped  without  any  attempt  made  to 
change  the  causes  for  the  delinquency,  the  case  will  undoubtedly  come 
up  again.  Most  institutions  are  overcrowded  and  not  properly  equipped 
for  the  necessary  training,  either  in  trained  personnel  or  the  mechanics 
of  handling  the  cases.  Probation  officers  are  comparatively  few  in 
number  and  not  particularly  well  trained.  Therefore,  the  limitations 
of  a  judge  of  a  juvenile  court  are  not  to  be  entirely  laid  at  his 
door. 

The  education  of  the  community  and  the  training  of  responsible  public 
opinion  to  demand  adequate  laws  and  adequate  budgets  for  carrying  out 
the  laws  are  absolutely  necessary  if  these  problems  of  conduct  during  the 
period  of  adolescence  are  to  be  adequately  handled.  To  gain  this  com- 
munity responsibility  psychopathic  centers  for  the  study  of  these  adoles- 
cent problems  are  essential.  At  such  centers,  the  best  scientific  medical 
and  psychological  studies  can  be  carried  out  on  these  individual  problems 
as  they  present  themselves.  More  than  that,  such  findings  must  be 
interpreted  for  and  to  the  public  in  language  understood  and  appreciated 
in  order  that  the  greatest  factor  in  the  whole  problem  of  adolescent  con- 
duct may  be  met,  the  factor  of  environment. 

Environment  is  after  all  a  lay  problem.  Only  the  very  few  in  com- 
parison to  the  need  can  have  carefully  planned  and  selected  environment. 
The  average  child  passes  his  adolescence  in  the  average  community  and 
that  community  must  be  educated  in  the  needs  and  problems  of  adoles- 
cence. The  average  community  expression  toward  the  adolescent  child 
is  either  shown  by  constant  repression  or  complete  ignoring  of  the  whole 
problem.  The  records  of  the  court  prove  this  beyond  any  doubt.  Case 
after  case  of  misconduct  on  the  part  of  both  girls  and  boys  record  the 
fact  of  stern  denial  on  the  part  of  parents  to  what  might  have  remained 
more  or  less  normal  activity  on  the  child's  part,  or  an  absolute  lack  of 
interest  in  or  knowledge  of  a  child's  activities,  which,  allowed  to  seek 


THE  TEACHING  OF  SOCIAL  HYGIENE  537 

their  own  levels  during  the  unstable  periods  of  adolescence,  ended  in 

broken  laws. 

The  physician's  part  is  first  of  all  the  patient  study  of  the  period  of 
adolescence  and  an  appreciation  of  its  effect  on  the  conduct  of   the 
individual.     But  his  responsibility  does  not  end  here.     The  education  of 
the  person  controlling  the  environment  of  the  individual  case  must  also 
be  undertaken  by  the  physician  if  the  results  of  his  study  are  to  be  effec- 
tive.    In  this  education  of  the  parent,  the  home,  and  the  community ,_  the 
physician  must  have  the  indispensable  service  of  the  medically  trained 
psychological  social  worker.    It  is  interesting  to  note  that  the  war  has 
stimulated  the  formation  of  a  course  of  training  at  Smith  College  for 
those  social  workers  interested  in  the  psychological  and  moral  problems. 
But  the  physician  himself  must  emphasize  and  help  interpret  to  the  com- 
munity the  broader  community  responsibilities.     The  kind  of  recreation 
offered  to  the  adolescent  child  of  any  given  community  becomes  the 
business  of  the  physician  because  it  is  part  of  his  treatment  to  recommend 
proper  recreation.     The  dearth  of  opportunities  for  proper  recreation 
immediately  appals  the  interested  physician.     Cheap  moving  pictures, 
dealing  in   so  many  instances   with  grotesque   and   vulgar   suggestive 
humor's  or  intense  sex  complications,  and  the  unsupervised  dance  halls 
make  the  problem  most  difficult  for  the  doctor.     The  adolescent  child 
needs  wholesome  out-of-door  exercise,  organized  to  permit  of  free  self- 
expression,  swimming  properly  supervised,  dancing,  dramatics.     Often 
the  child  of  the  poor  is  better  off  in  these  respects  than  the  child  ot 
moderate  circumstances  or  of  the  rich.    The  settlement  houses  long  ago 
recognized  these  problems  and  the  club  life  of  settlements  has  been  the 
attempt  to  meet  them. 

The  Teaching  of  Social  Hygiene 

"  The  war  has  forced  the  issue  in  sex  education."  These  words  of 
Dr  Mabel  Ulrich  in  her  telling  pamphlet,  ''  Mothers  of  America,"  give 
the  reason  for  this  discussion  here  C).  The  past  two  years  of  public 
government  propaganda  has  brought  the  subject  of  social  hygiene  out 
of  the  field  of  private  endeavor  to  that  of  a  distinct  public  health  educa- 
tional basis.  When  the  Surgeon  General's  Office  C)  issues  such  facts 
as  these,  namely,  that  syphilis  and  gonorrhea  have  disabled  more  men  in 
our  army  and  navy  than  all  other  diseases  combined,  that  the  draft  has 
proved  these  diseases  to  be  more  frequent  among  the  boys  from  our  own 
home  towns  than  among  those  in  the  regular  army,  and  that  in  spite  ot 
all  that  was  done  to  prevent  contagion,  at  least  125,000  new  cases  devel- 
oped among  our  drafted  boys,  the  field  of  social  hygiene  has  become  one 


538  ADOLESCENCE 

of  the  most  burning  of  the  pubhc  issues.  Here  we  are  concerned  with 
two  aspects  of  the  question:  the  relation  of  preventive  medicine  to  the 
field  and  its  bearing  upon  adolescence;  and  the  relation  of  adolescence  to 
social  hygiene.  The  pre-adolescent  period  is  the  time  in  which  the  foun- 
dation of  the  education  in  sex  hygiene  should  be  laid.  It  is  then  that  the 
questions  as  to  the  whys,  wheres,  and  hows  of  life  are  asked  and  upon 
the  frank  meeting  of  these  questions  depends  the  future  of  adolescent 
attitude.  If  before  ten,  the  child  has  met  honest,  frank  answers  to  his 
questions,  the  later  sex  problems  are  the  more  readily  approached  with 
frankness  and  a  minimum  of  sex  consciousness. 

The  importance  of  the  pre-adolescent  question  as  to  how  life  is 
created,  does  not  lie  so  much  in  the  information  given  in  the  honest 
answer,  but  in  the  frankness  and  beauty  with  which  the  question  is 
discussed,  the  maintenance  of  the  unconscious  curiosity  of  the  child. 
Sex  consciousness,  as  such,  seldom  enters  into  the  natural  curious  in- 
quiry of  the  child  under  ten.  Sex  then  is  merely  accidental,  the  why  is 
asked  about  everything  which  brings  new  life ;  babies  simply  fall  naturally 
into  the  category  of  interesting  new  life  that  is  introduced  into  the  child's 
immediate  environment.  It  is  the  same  with  a  new  kitten  or  calf.  The 
truth  is  wanted  and  should  be  given  at  the  period,  but  it  bears  no  personal 
relation  to  the  child,  while  the  way  in  which  he  is  answered  makes  the 
more  lasting  impression.  The  pre-adolescent  period  has  been  left  largely 
to  the  ignorance  or  lack  of  understanding  of  parents,  and  the  curiosity 
of  other  children,  which  has  brought  to  the  adolescent  period  a  false 
impress.  Preventive  medicine  must  begin  its  work  in  the  pre-adolescent 
period  if  it  is  to  have  any  comprehensive  effect  on  the  adolescent  period. 

It  is  the  business  of  the  physician  to  stimulate  the  parents  to  equip 
themselves  to  meet  these  intimate  problems  of  the  children.  This  can  be 
done  largely  by  intelligent  direction  on  his  part  to  the  available  literature 
on  the  subject,  and  by  giving  to  the  parents  his  own  comprehensive  idea 
of  the  subject.  The  child  under  ten  grasps  little  of  the  detail  of  the  infor- 
mation given  him  but  the  dramatic  points,  the  frank  intimacy  shared  by 
him  and  his  parents  are  his  best  preparation  for  the  sex  consciousness  of 
the  adolescent  period.  The  adolescent  period  marks  the  beginning  of  his 
consciousness  that  these  questions  that  have  stirred  his  curiosity  and 
imagination  are  personal  sex  problems  and  that  he  must  establish  his 
relationship  with  them.  This  sex  consciousness  results  often  in  that 
impenetrable  reserve,  often  the  attitude  almost  of  fear,  that  causes  many 
of  the  complex  psychoses  of  adolescence.  Information  may  be  given  at 
different  times  with  varying  degrees  of  detail  to  meet  the  particular  prob- 
lem facing  the  individual  but  the  chief  problem  is  to  so  relate  the  child  to 
the  whole  life  concept  that  sex  becomes  more  and  more  a  normal  part  of  a 


THE  TEACHING  OF  SOCIAL  HYGIENE  539 

normal  whole.  The  best  time  to  differentiate  sex  distinction  in  a  child's 
mind  is  before  he  becomes  conscious  of  himself  as  of  a  sex.  When  adoles- 
cence comes,  the  avenue  of  approach  to  sex  hygiene  should  be  social 
rather  than  personal.  At  no  time  in  life  is  the  need  of  a  background 
of  law  more  needed  or  more  helpful  than  during  the  unstable  years  of 
adolescence.  One  of  the  most  clear  and  concise  expressions  of  this  is 
set  forth  in  that  splendid  "  Children's  Code  "  prepared  by  William  J. 
Hutchins  C).  The  theme  of  the  code  is  patriotism  expressed  in  conduct. 
The  code  is  given  in  full  because  it  states  in  the  fewest  words  the  con- 
structive preventive  program  for  the  adolescent  period : 

"  Boys  and  girls  who  are  good  Americans  try  to  become  strong  and 
useful,  that  our  country  may  become  ever  greater  and  better.  Therefore 
they  obey  the  laws  of  right  living  which  the  best  Americans  have  always 
obeyed. 

"  The  Good  American  Tries  to  Gain  and  to  Keep  Perfect  Health. — 
The  welfare  of  our  country  depends  upon  those  who  try  to  be  physically 
fit  for  their  daily  work.  Therefore :  i.  I  will  keep  my  clothes,  my  body, 
and  my  mind  clean.  2.  I  will  avoid  those  habits  which  would  harm  me, 
and  will  make  and  never  break  those  habits  which  will  help  me.  3.  I  will 
try  to  take  such  food,  sleep,  and  exercise  as  will  keep  me  in  perfect 
health. 

"  The  Good  American  Controls  Himself. — Those  who  best  control 
themselves  can  best  serve  their  country,  i.  I  will  control  my  Tongue, 
and  will  not  allow  it  to  speak  mean,  vulgar,  or  profane  words.  2.  I 
will  control  my  Temper,  and  will  not  get  angry  when  people  or  things 
displease  me.  3.  I  will  control  my  Thoughts,  and  will  not  allow  a  foolish 
wish  to  spoil  a  wise  purpose. 

"  The  Good  American  is  Reliable. — Our  country  grows  great  and 
good  as  her  citizens  are  able  more  fully  to  trust  each  other.  Tlierefore: 
I.  I  will  be  honest,  in  word  and  in  act.  I  will  not  lie,  sneak,  or  pretend, 
nor  will  I  keep  the  truth  from  those  who  have  a  right  to  it.  2.  I  will  not 
do  wrong  in  the  hope  of  not  being  found  out.  I  cannot  hide  the  truth 
from  myself  and  cannot  often  hide  it  from  others.  3.  I  will  not  take 
without  permission  what  does  not  belong  to  me.  4.  I  will  do  promptly 
what  I  have  promised  to  do.  If  I  have  made  a  foolish  promise,  I  will 
at  once  confess  my  mistake,  and  I  will  try  to  make  good  any  harm  which 
my  mistake  may  have  caused.  I  will  so  speak  and  act  that  people 
will  find  it  easier  to  trust  each  other. 

"  The  Good  American  Plays  Fair. — Clean  play  increases  and  trains 
one's  strength,  and  helps  one  to  be  more  useful  to  one's  country.  There- 
fore:  I.  I  will  not  cheat,  nor  will  I  play  for  keeps  or  for  money.     If  I 


540  ADOLESCENCE 

should  not  play  fair,  the  loser  would  lose  the  fun  of  the  game,  and  the 
winner  would  lose  his  self-respect,  and  the  game  itself  would  become  a 
mean  and  often  cruel  business.  2.  I  will  treat  my  opponent  with  polite- 
ness. 3.  If  I  play  in  a  group  game,  I  will  play,  not  for  my  own  glory, 
but  for  the  success  of  my  team  and  the  fun  of  the  game.  4.  I  will  be  a 
good  loser  or  a  generous  winner. 

"  The  Good  American  Does  His  Duty. — The  shirker  or  the  willing 
idler  lives  upon  the  labor  of  others,  burdens  others  with  the  work  which 
he  ought  to  do  himself.  He  harms  his  fellow  citizens,  and  so  harms  his 
country,  i.  I  will  try  to  find  out  what  my  duty  is,  WHAT  I  OUGHT 
TO  DO,  and  my  duty  I  will  do,  whether  it  is  easy  or  hard.  What  I  ought 
to  do  I  can  do. 

""  The  Good  American  Tries  to  Do  the  Right  Thing  in  the  Right  Way. 
— The  welfare  of  our  country  depends  upon  those  who  have  learned  to  do 
in  the  right  way  the  things  that  ought  to  be  done.  Therefore:  i.  I  will 
get  the  best  possible  education,  and  learn  all  that  I  can  from  those  who 
have  learned  to  do  the  right  thing  in  the  right  way.  2.  I  will  take  an 
interest  in  my  work,  and  will  not  be  satisfied  with  slip-shod  and  merely 
passable  work.  A  wheel  or  a  rail  or  a  nail  carelessly  made  may  cause 
the  death  of  hundreds.  3.  I  will  try  to  do  the  right  thing  in  the  right 
way,  even  when  no  one  else  sees  or  praises  me.  But  when  I  have  done 
my  best,  I  will  not  envy  those  who  have  done  better,  or  have  received 
larger  reward.     Envy  spoils  the  work  and  the  worker. 

"  The  Good  American  Works  in  Friendly  Cooperation  with  His 
Fellow-workers. — One  man  alone  could  not  build  a  city  or  a  great  rail- 
road. One  man  alone  would  find  it  hard  to  build  a  house  or  a  bridge. 
That  I  may  have  bread,  men  have  sowed  and  reaped,  men  have  made 
plows  and  threshers,  men  have  built  mills  and  mined  coal,  men  have  made 
stoves  and  kept  stores.  As  we  learn  better  how  to  work  together  the 
welfare  of  our  country  is  advanced,  i.  In  whatever  work  I  do  with 
others,  I  will  do  my  part  and  will  help  others  do  their  part.  2.  I  will 
keep  in  order  the  things  which  I  use  in  my  work.  When  things  are 
out  of  place,  they  are  often  in  the  way,  and  sometimes  they  are  hard  to 
find.  Disorder  means  confusion,  and  the  waste  of  time  and  patience.  3. 
In  all  my  work  with  others,  I  will  be  cheerful.  Cheerlessness  depresses 
all  the  workers  and  injures  all  the  work.  4.  When  I  have  received  money 
for  my  work,  I  will  be  neither  a  miser  nor  a  spendthrift.  I  will  save  or 
spend  as  one  of  the  friendly  workers  of  America. 

"  The  Good  American  is  Kind. — In  America  those  who  are  of  dif- 
ferent races,  colors,  and  conditions  must  live  together.  We  are  of  many 
different  sorts,  but  we  are  one  great  people.  Every  unkindness  hurts  the 
common  life,  every  kindness  helps  the  common  life.     Therefore:  i.  I 


THE  TEACHING  OF  SOCIAL  HYGIENE  541 

will  be  kind  in  all  my  Thoughts.  I  will  bear  no  spites  or  grudges.  I 
will  not  think  myself  above  any  other  girl  or  boy  just  because  I  am  of 
different  race  or  color  or  condition.  I  will  never  despise  anybody.  2.  I 
will  be  kind  in  all  my  Speech.  I  will  not  gossip  nor  will  I  speak  unkindly 
of  anyone.  Words  may  wound  or  heal.  3.  I  will  be  kind  in  all  my  Acts. 
I  will  not  selfishly  insist  on  having  my  own  way.  I  will  always  be  polite. 
Rude  people  are  not  good  Americans.  I  will  not  trouble  unnecessarily 
those  who  do  work  for  me.  I  will  do  my  best  to  prevent  cruelty,  and 
will  give  my  best  help  to  those  who  need  it  most. 

"  The  Good  American  is  Loyal. — If  our  America  is  to  become  ever 
greater  and  better,  her  citizens  must  be  loyal,  devotedly  faithful,  in  every 
relation  of  life.  i.  I  will  be  loyal  to  my  family.  In  loyalty  I  will  gladly 
obey  my  parents  or  those  who  are  in  their  place.  I  will  do  my  best  to 
help  each  member  of  my  family  to  strength  and  usefulness.  2.  I  will  be 
loyal  to  my  school.  In  loyalty  I  will  obey  and  help  other  pupils  to  obey 
those  rules  which  further  the  good  of  all.  3.  I  will  be  loyal  to  my  town, 
my  state,  and  my  country.  In  loyalty  I  will  respect  and  help  others  to 
respect  their  laws  and  their  courts  of  justice.  4.  I  will  be  loyal  to 
humanity.  In  loyalty  I  will  do  my  best  to  help  the  friendly  relations  of 
our  country  with  every  other  country,  and  to  give  to  everyone  in  every 
land  the  best  possible  chance. 

"  If  I  try  simply  to  be  loyal  to  my  family,  I  may  be  disloyal  to  my 
school.  If  I  try  simply  to  be  loyal  to  my  school,  I  may  be  disloyal  to 
my  town,  my  state,  and  my  country.  If  I  try  simply  to  be  loyal  to  my 
town,  state,  and  country,  I  may  be  disloyal  to  humanity.  I  will  try  above 
all  things  else  to  be  loyal  to  humanity ;  then  I  shall  surely  be  loyal  to 
my  country,  my  state,  and  my  town,  to  my  school,  and  to  my  family." 

Thus  are  given  the  social  objectives  by  which  the  youth  hitches  his 
sex  consciousness  to  the  stars ! 

At  the  same  time  sex  consciousness  has  its  very  definite  physical 
aspects  and  developments  and  these  must  be  explained  and  understood. 
But  all  this  is  more  possible  when  the  child's  relation  to  the  larger  physical 
and  social  life  has  been  firmly  developed  in  him.  Adolescence  is  not  a 
pleasant  period  for  a  child — change  and  upheaval  seldom  are.  But  the 
awakening  of  the  sex  life  is  for  the  great  purpose  of  reproduction  and 
even  though  the  adolescent  child  may  have  no  personal  interest  as  yet  in 
that  great  purpose,  he  may  be  appealed  to  to  play  the  game  fairly  in  order 
that  he  may  do  his  part  when  the  time  comes.  The  period  of  adolescence 
always  necessitates  a  restatement  of  the  facts  of  life  and  then  they  are 
related  to  the  new  sex  development;  physical  rightness  is  the  aspect  to 
be  most  thoroughly  emphasized  because  of  its  wider  social  responsibility. 


542  ADOLESCENCE 

The  old  method  of  fear  and  penalties  for  breaking  rules  of  health  is  not 
to  be  employed  during  the  adolescent  period,  particularly  because  of  the 
bad  psychical  effects.  The  constructive  side  is  always  to  be  emphasized. 
In  the  mass  of  literature  on  this  subject  certain  publications  stand  out 
with  refreshing  strength  and  wisdom  along  these  lines.  The  Arm- 
strongs' C)  pamphlets  for  boys  and  girls  from  twelve  to  sixteen  years: 
"  Sex  in  Life  "  and  "Sex  in  Life,  the  Development  of  the  Mind  and 
Will,"  are  of  the  best,  and  a  vigorous  contribution  to  preventive  medicine. 
Doctor  Ulrich's  (")  booklets  are  a  happy  combination  of  the  physical 
problems  of  adolescence  and  their  immediate  bearing  upon  the  purpose 
of  life  and  its  responsibilities.  Sex  hygiene  is  social  hygiene,  and  in  the 
teaching  of  it  there  must  be  constant  recognition  of  the  constant  relation 
of  the  individual  to  the  social  group.  The  petulant  remark  of  a  nervous 
girl  during  her  adolescence,  "  I  don't  care  what  organs  I  have — I  want 
to  know  why  I  feel  as  I  do,"  is  natural  and  characteristic  of  the  period. 
The  most  carefully  selected  and  frank  information  along  physical  lines 
leaves  the  feelings  untouched,  and  feelings  are  but  the  golden  links  be- 
tween the  physical  facts  of  life  and  the  social  purpose. 

Kirkpatrick  states  in  that  illuminating  book,  "  The  Individual  in  the 
Making,"  "  never  does  one  feel  so  vividly  that  he  can  be  anything  or  do 
anything  that  he  desires.  This  assurance  should  and  often  does  lead  to 
immediate  direction  of  effort  toward  ends  that  are  desired  C^)."  Thus 
the  teaching  of  social  hygiene  becomes  a  great  incentive  in  the  field  of 
preventive  medicine  to  a  more  clear-cut  development  of  the  many  physi- 
cal, anatomical  and  psychological  changes  of  the  adolescent.  The  period 
gains  in  the  strength  of  its  "  finalities  "  by  the  careful,  intelligent  relation 
of  all  its  variableness  to  the  great  social  purposes  of  life. 

BIBLIOGRAPHY 
Direct  Text  References 

1.  MOSHER,   CLELIA   DUEL:   Health   and  the   Woman   Movement.     Nat. 

Board  Y.  W.  C.  A.,  1916,  11. 

2.  HEALY,  WILLIAM:   The   Individual   Delinquent.     Little,   Brown  &   Co., 

1915- 

3.  MARINE,   DAVID,  and  KIMBALL,   O.   P.:  Jour.   Lab.   and   Clin.   Med., 

1917,  III,  40. 

4.  ROBERTSON,  T.  BRAILSFORD:  Endocrinology,  1917,  I,  30. 

5.  ULRICH,  MABEL  S.:  Mothers  of  America.    Minn.  State  Board  of  Health, 

Division  of  Venereal  Diseases,  1918,  5. 

6.  ULRICH,  MABEL  S.:  Mothers  of  America.    Minn.  State  Board  of  Health, 

Division  of  Venereal  Diseases,  1918,  3. 

7.  HUTCHINS,  WILLIAM  J.:  The  Children's  Code  of  Morals.     University 

Society,  New  York  City. 


BIBLIOGRAPHY  543 

8.  ARMSTRONG,  DONALD  B,  and  EUNICE  B.:  Sex  in  Life,  Soc.  Hyg., 

1916,  II,  331 ;  Sex  in  Life,  Development  of  Mind  and  Will,  Pamphlet 
No.  2,  ibid.,  549. 

9.  ULRICH,  MABEL  S.:  Uncle  Sam  Needs  Leaders:  The  Girl's  Part.    Minn. 

State  Board  of  Health,  1918. 
10.    KIRKPATRICK,  E.  A. :  The  Individual  in  the  Making.    Houghton,  Mifflin 
Co.,  191 1,  249. 

General  Chapter  References 

BEEKMAN,  F.:  Arch,  of  Pediat.,  1915,  XXXII,  4. 

BELL,  W.  BLAIR:  The  Sex  Complex.    Balliere,  Tendall  &  Cox,  London,  1916. 

BENEDICT,  FRANCIS  G.:  Boston  Med.  and  Surg.  Jour.,  1919,  CLXXXI,  107. 

BIEDL,  ARTHUR:  The  Internal  Secretory  Organs.     Wood,  New  York,  1913. 

BRIDGMAN,  OLGA  L.:  Boston  Med.  and  Surg.  Jour.,  1918,  CLXXIX,  505. 

CANNON,  W.  B.:  Endocrinology,  1917,  I,  50. 

ELLIS,  HAVELOCK:  Studies  in  the  Psychology  of  Sex.     Davis,  Philadelphia, 

1910. 
ENGELMANN,  G.  J.:  Jour.  Am.  Med.  Assoc,  1901,  XXXVI,  1,650. 
GEPHART,  F.  C:  Boston  Med.  and  Surg.  Jour.,  1917,  CLXVI,  107. 
GODIN,  PAUL:  Comptes  Med.  des  Seances  de  I'Acad.  des  Sciences,  191 1,  CLIII, 

967;  191 2,  CLV,  66. 
GULICK,  LUTHER  HALSEY,  and  AYRES,  LEONARD  P. :  Medical  Inspec- 
tion of  Schools,  N.  Y.  Charities  Pub.  Com.,  1910. 
GARRIGUES,  HENRY  J.:  A  Text  Book  of  the  Diseases  of  Women,  3d  ed., 

Saunders,  Philadelphia,  1910. 
GUYER,  MICHAEL  F.:  Being  Well  Born.    Bobbs,  Merrill,  1916. 
HALL,  G.  STANLEY:  Adolescence,  I  and  II.    Appleton,  New  York,  1916. 
HALL,  W.  S.:  Am.  Acad,  of  Med.,  Bull.,  1914,  XV,  86. 
LATIMER,  CAROLINE  WORMLEY :  Girl  and  Woman,  1909. 
LOMBROSO,  CESARE:  Revue  de  Psych.,  1901. 

McDOUGAL,  WILLIAM :  Social  Psychology.    John  W.  Lucas  &  Co.,  1916. 
MORRO:  "Le  Puberte." 
OSBORNE,  T.  B.,  and  MENDEL,  LAFAYETTE  B.:  Jour.  Biol.  Chem.,  1914, 

XVIII,  95;  Am.  Jour.  Phys.,  1916,  XL,  16. 
PIERSOL,  GEORGE  A.:  Human  Anatomy,  5th  ed.     Lippincott,  Philadelphia, 

1907. 
PUFFER,  J.  ADAMS :  The  Boy  and  His  Gang. 
ROBERTSON,  T.  BRAILSFORD:  Am.  Jour.  Phys.,  1915,  XXXVII,  74;  Am. 

Jour.  Phys.,  1916,  XLI,  547. 
ROTCH,    THOMAS    MORGAN:    Living    Anatomy    and    Pathology    by    the 

Roentgen  Method.    Lippincott,  1910. 
SEITZ,  PROF.  C:  Diseases  of  Puberty,  111-130,  Pfaundler  and  Schlossmann. 

Lippincott,  1908. 
STARR,  LOUIS:  The  Adolescent  Period.    Blakeston,  Philadelphia,  1915. 
TALBOT,  FRITZ  B.:  Am.  Jour.  Dis.  of  Ch.,  1919,  XVIII,  229. 
TYLER,   JOHN    MASON:    Growth   and   Education.     Houghton,    Mifflin   Co., 

Boston,  1907. 
VINCENT,  SWALE:  Internal  Secretions  and  the  Ductless  Glands.     London, 

1912. 


CHAPTER   XIV 
AVIATION    MEDICINE 

By  LOUIS  HOPEWELL   BAUER 

Table  of  Contents 

Introduction 545 

Aviation  Medicine 547 

The  Flight  Surgeon 547 

Varieties  of  Flying 547 

Physical  Requirements  of  Flying.      .      .      .> 549 

The  Eye 550 

The  Ear,  Nose  and  Throat 558 

Equilibrium 559 

General  Physical  Requirements 561 

Nervous  System 563 

Neurological  Examination 563 

Psychic  Examination 563 

Reaction  of  Time  and  Flying  Aptitude 566 

Periodicity  of  Examinations 570 

Physical  Defect  and  Flying  Ability 570 

Effects  of  High  Altitude 573 

Aero  Embolism  and  Emphysema 576 

Effects  of  High  Speed 577 

Effects  of  Cold  and  Wind 578 

Blind  Flying 579 

Care  of  the  Flyer  582 

Fatigue 582 

Staleness 582 

Schneider  Index 586 

Flying  Time  for  Pilots 587 

Air  Sickness 589 

Bibliography 591 

Introduction 

Aviation  is  a  comparatively  new  subject  which  had  its  orie;in  in  the 
rapid  development  of  aeronautics  which  took  place  during  the  first  World 
War.  Except  for  the  effects  of  high  altitude,  as  observed  in  mountain 
expeditions  and  certain  researches  on  the  vestibular  mechanism,  nothing 

COPYRIGHT    1943    BY    THE   OXFORD    UNIVERSITY   PRESS,    NEW    YORK,    INC. 

545 


546  AVIATION   MEDICINE 

was  known  pertaining  to  the  physiology  of  flight.  Man  was  not  designed 
by  nature  to  fly  and  hence,  what  its  effect  on  him  might  be,  had  hardly 
been  considered. 

In  the  early  days  of  flying,  at  the  time  of  the  Wright  brothers'  epochal 
accomplishment  and  for  some  time  thereafter,  flying  was  hardly  even  a 
science.  A  man  was  taught  what  he  could  be  taught  on  the  ground,  and 
then  he  tried  to  apply  it  in  the  air.  If  he  were  lucky,  he  flew.  If  he  were 
unlucky,  he  was  killed  or  severely  injured.  The  one  physical  attribute 
considered  necessary  was  "nerve",  and  there  is  no  doubt  that  it  took 
plenty  of  that. 

Development  in  aeronautics  was  desultory  until  the  first  World  War 
broke  out,  and  then  the  possibilities  of  flying  from  a  military  standpoint 
were  so  impressed  on  the  Allies  and  the  Central  Powers  that  a  tremen- 
dous advance  was  made  from  the  mechanical  standpoint.  ,  The  physical 
factor  still  was  not  considered  especially  important.  Only  the  ordinary 
physical  examinations  were  required  for  duty  in  aviation  services.  Soon, 
however,  it  became  apparent  that  there  were  many  accidents  from  a 
physical  cause.  Pilots  were  wearing  out  too  fast,  and  there  were  too 
many  deaths  attributable  to  physical  causes.  Research  work,  stimulated 
by  the  necessity  of  man-power  conservation,  indicated  that  certain  factors 
of  a  physical  nature,  not  important  in  ground  fighting,  were  paramount 
in  the  air. 

Gradually,  therefore,  special  examinations  developed  which  became 
more  or  less  similar  in  all  countries.  By  the  time  the  United  States  en- 
tered the  war  much  experience  in  the  subject  had  been  gained  by  the 
Allies  of  benefit  to  our  own  country.  As  would  be  expected,  many  mis- 
takes were  made;  stress  was  laid  where  it  should  not  have  been  in  some 
instances,  and  other  points  which  should  have  been  stressed  were  over- 
looked. 

Following  the  war  civil  aeronautics  began  to  develop  in  Europe,  al- 
though it  was  not  until  1927  that  any  progress  was  made  in  this  country. 
It  was  found  that  civil  flying  is  somewhat  different  in  its  demands  from 
military  flying  and  consequently,  the  regulations  had  to  be  modified. 
With  the  development  of  transport  planes  with  their  complicated  in- 
strument panels  and  safety  devices,  with  the  increasing  altitude  of  flight 
including  flights  into  the  stratosphere  and  with  the  steadily  increasing 
speed  of  planes,  the  medical  aspects  of  flying  became  increasingly  im- 
portant. Finally,  with  the  development  of  high  altitude  bombing  and 
dive-bombing,  the  resulting  onset  of  aero  embolism  and  emphysema  and 
the  damaging  effects  of  marked  centrifugal  force,  new  problems  have  had 
to  be  conquered. 

Vol.  I.  343 


VARIETIES  OF  FLYING  547 

Definitions.  —  Aviation  Medicine.  —  Out  of  a  mass  of  experience,  re- 
search and  statistics  a  subject  known  now  as  aviation  medicine  has 
developed  as  a  distinct  specialty.  This  specialty  is  really  a  branch  of  pre- 
ventive medicine,  as  its  sole  basis  is  the  prevention  of  aircraft  accidents 
from  the  human  standpoint.  It  has  drawn  to  itself  portions  of  other 
specialties,  namely,  physiology,  internal  medicine,  ophthalmology,  otology, 
neuropsychiatry  and  psychology.  It  is  a  correlation  of  certain  parts  of 
these  specialties  as  they  relate  to  flying.  The  specialist  in  aviation  medi- 
cine is  known  as  the  flight  surgeon. 

The  Flight  Surgeon.  —  The  flight  surgeon  is  a  physician  trained  in 
aviation  medicine.  He  is  familiar  with  the  branches  of  medicine  con- 
cerned with  aeronautics  and  their  application  thereto.  He  is  skilled  in 
making  the  various  examinations  required.  He  is  sufficiently  familiar 
with  flying  and  its  attendant  strains  and  stresses  to  be  a  useful  medical 
advisor  to  pilots  and  operators.  He  is  familiar  with  the  effects  of  oxygen 
want  and  lowered  barometric  pressure;  he  knows  the  effects  of  increased 
gravity  drags  on  the  human  body,  and  he  knows  how  by  applying  his 
special  knowledge  he  can  prevent  accidents  from  a  physical  standpoint  by 
careful  selection  and  careful  supervision  of  flying  personnel. 

The  flight  surgeon  is  preferably  a  fairly  young  man,  as  most  flyers  are 
young,  and  they  are  more  apt  to  make  a  confidant  of  one  not  too  old. 
His  personality  must  be  one  to  inspire  confidence  and  respect. 

He  should  fly  under  all  conditions  and  with  all  types  of  pilots.  The 
flight  surgeon,  who  remains  on  the  ground,  gets  scant  consideration  from 
the  flying  personnel.  He  must  experience  the  conditions  the  flyer  meets 
almost  daily  in  order  to  appreciate  them  and  be  competent  to  advise 
regarding  their  effect.  He  must  have  a  thorough  grounding  in  physiology 
of  respiration  and  circulation,  in  psychiatry  and  psychology,  in  internal 
medicine,  and  he  must  know  sufficient  ophthalmology  to  make  the  special 
examinations  required  and  interpret  their  results. 

Varieties  of  Flying 

Flying  is  divided  into  heavier-than-air  and  lighter-than-air.  Heavier- 
than-air  flying  is  divided  into  military,  civilian  and  glider,  which  may  be 
either  military  or  civilian,  and  civilian  flying  into  airline,  commercial  and 
sport  flying. 

The  requirements  vary  according  to  the  type  of  flying  to  be  done. 

Military.  —  Military  flying  is  divided  into  fighting,  formerly  known 
as  pursuit,  air  support  and  bombing.  There  are  three  types  of  bombers, 
light,  medium  and  heavy. 

Vol.  I.  343 


548  AVIATION   MEDICINE 

Pursuit.  —  Acrobatic  flying,  which  we  sometimes  think  of  as  stunt 
flying,  is  absolutely  essential  for  a  military  pilot.  For  the  combat  pilot 
it  is  life-saving.  The  pursuit  or  fighter  plane  is  fast  and  easily  maneu- 
verable.  It  is  a  single  seater.  The  pilot's  decisions  must  be  automatic. 
He  must  always  be  one  jump  ahead  of  his  opponent.  His  vision  must  be 
perfect.  He  must  be  able  to  identify  other  aircraft  in  the  air  often  by 
silhouette  alone.  His  depth  perception  must  be  perfect,  as  he  flies  in 
formation  with  only  a  few  feet  between  wing  tips.  His  reaction  time  must 
be  immediate,  and  his  coolness  in  danger  is  absolutely  essential.  The 
fighter  pilot  must  not  only  be  a  flyer  but  a  gunner. 

Air  Support.  —  This  includes  military  flying  not  covered  by  the 
fighters  and  bombers.  It  includes  support  of  the  ground  troops  with 
attack  by  machine  guns  and  small  bombs. 

Bombardment.  —  This  has  become  more  complicated  during  the  present 
war.  The  heavy  bombers  are  4  motored  ships  and  virtually  flying  for- 
tresses with  a  crew  of  several  men,  including  pilot,  co-pilot,  navigator, 
radioman,  gunners  and  bombardiers.  They  fly  at  high  altitudes  and  for 
long  distances.  Then  there  are  the  medium  bombers,  which  are  faster 
but  have  a  shorter  range  and  are  small.  They  are  used  for  either  hori- 
zontal or  dive-bombing.  In  dive-bombing  the  planes  swoop  down  from 
a  high  altitude,  drop  th^ir  bombs  and  zoom  up  again.  These  pilots  are 
subject  to  change  of  direction  at  speeds  up  to  500  miles  an  hour.  Light 
bombers  fly  at  low  altitudes  and  attack  troops. 

Naval.  —  Naval  pilots,  besides  the  above,  have  to  learn  to  land  on  the 
deck  of  a  carrier  which  calls  for  coolness  and  excellent  depth  perception. 
Landing  on  the  water  calls  for  more  accurate  depth  perception  than  land- 
ing on  land. 

As  a  whole  military  flying  is  a  young  man's  game,  fighter  and  dive 
bombing  flying  calling  for  the  greatest  skill,  quickest  reaction  time, 
greatest  daring  and  coolness.  Long  and  moderate  distance  high  altitude 
bombing  probably  are  a  close  second. 

Civil  Flying.  —  Civil  flying  in  the  United  States  is  divided  into  three 
classes,  (i)  air-line,  (2)  commercial  and  commercial  lighter-than-air  and 
(3)  private,  student  ^nd  private  or  student  lighter-than-air  and  free 
balloon. 

The  air-line  pilot  flies  commercial  transport  planes,  day  and  night, 
over  scheduled  air  routes.  He  is  responsible  for  passengers,  mail,  freight 
and  property.  He  must  be  an  accomplished  pilot,  navigator,  radioman 
and  blind  flyer. 

The  commercial  pilot,  either  heavier  or  lighter-than-air,  carries  pas- 
sengers and  often  is  an  instructor.     He  may  be  a  co-pilot  on  an  air-line. 

Vol.  I.  343 


PHYSICAL    REQUIREMENTS  549 

The  private  pilot  may  fly  for  his  own  amusement  or  recreation  but 
may  not  engage  in  any  phase  of  commercial  flying. 

The  student,  of  course,  is  the  novice  learning  to  fly.  He  must  take 
his  instruction  from  a  licensed  commercial  pilot  and  in  a  licensed  plane. 

The  air  line  or  commercial  pilot  does  not,  in  fact,  he  is  forbidden  to, 
indulge  in  acrobatics  while  flying  commercially.  He  flies  over  known 
territory  adequately  equipped  with  landing  fields  and  beacons  and  the  air 
line  pilot  in  addition,  flies  on  a  radio  beam.  He  may  strike  bad  weather, 
but  an  efficient  meteorological  service  keeps  him  in  touch  with  weather 
conditions.  His  responsibility  is  heavy,  however,  as  he  has  the  ^ves  of 
nassengers  in  his  hands.  Often  his  flying  is  done  at  night.  While  com- 
mercial flying  does  not  call  for  quite  the  same  qualifications  as  certain 
phases  of  military  flying,  nevertheless  it  does  call  for  physical  soundness 

and  technical  proficiency.  ,  .u      r         .u^ 

The  commercial  pilot  is  a  potential  transport  pilot,  and  therefore,  the 

same  applies  to  him.  ,      .     ,  .     j  ^u 

The  private  pilot  may  reasonably  have  a  lower  physical  standard  than 
the  transport  grade.  He,  however,  must  meet  a  standard  that  insures  his 
not  being  a  menace  to  other  flyers  and  the  general  public. 

Blind  flying  has  become  essential  for  air  line  pilots  in  order  to  insure 
safety  in  unexpected  or  expected  poor  weather  conditions  or  above  the 
clouds.  Transport  flying  is  fatiguing  and  calls  for  endurance  and  sober 
iudgment  as  well  as  constant  alertness  and  keenness. 

Taken  as  a  whole,  air-line  flying  and  military  flying  are  equally  difficult 
and  call  for  the  highest  type  of  physical  and  mental  makeup. 

Lighter-than-air. -Lightcr-than-aW  flying  pertains  to  airships,  diri- 
gibles and  blimps,  and  to  balloons.  The  general  physical  requirements 
need  not  be  so  high,  in  that  visual  defects  may  be  corrected  with  glasses. 
Minor  structural  defects  may  be  passed  also. 

Glider  Pilots.  -  Glider  pilots  fly  motorless  planes.  Originally  this  was 
a  sport  only.  Now,  however,  it  has  become  a  military  function  also,_  as 
often  great  fleets  of  gliders  are  used  to  transport  troops.  The  physical 
qualifications  of  glider  pilots  have  not  been  definitely  set,  but  they  should 
be  at  least  those  of  private  pilots. 

Physical  Requirements  of  Flying 

At  the  present  time  we  may  group  the  physical  standards  of  aero- 
nautics into  two  distinct  classes.  First,  the  standard  for  the  military 
pilot  and  the  commercial  pilot  and  second,  the  standard  for  the  private  or 
sport  pilot. 

Vol."  I.  343 


550  AVIATION   MEDICINE 

The  detailed  requirements  may  be  obtained  in  the  regulations  of  the 
various  countries.  They  vary  somewhat  but  more  in  methods  of  examina- 
tion than  in  actual  standards.  In  this  chapter  we  shall  discuss  require- 
ments in  general  rather  than  in  detail. 

The  Eye 

Central  Vision.  —  It  is  recognized  both  by  the  physicians  concerned 
and  by  successful  pilots  that  good  vision  is  a  prime  necessity.  Not  only 
is  it  of  importance  to  the  military  pilot,  who  has  fighting,  bombing  or 
reconnaissance  to  carry  out,  but  it  is  important  to  any  flyer.  Traffic  in 
the  air  is  rather  congested  at  many  airports,  and  the  obstructions  around 
many  airports  are  not  always  easily  seen.  Planes  in  the  air  must  be  de- 
tected. When  two  ships  are  traveling  at  a  rate  of  well  over  300  miles 
per  hour,  they  cannot  be  seen  by  each  other  too  promptly.  By  good 
vision  is  meant  normal  vision  without  correction.  Corrected  vision,  while 
permitted  in  the  private  pilot,  is  a  poor  substitute  for  good,  uncorrected 
vision.  Corrections  worn  in  goggles  are  very  unsatisfactory,  as  they  cor- 
rect only  straight  ahead  vision,  and  when  misted  or  fogged,  necessitating 
their  removal,  the  pilot  is  rendered  helpless.  Furthermore,  the  wearing 
of  corrected  goggles  restricts  the  peripheral  field  of  vision.  With  the 
development  of  cabin  planes  there  is  less  objection  to  moderate  corrections 
being  worn  as  glasses. 

Practically  all  countries  require  for  military  and  air  line  pilots  normal 
or  20/20  vision  in  each  eye  uncorrected.  Some  countries,  notably  France, 
Holland  and  Hungary,  permit  one  eye  to  be  25  per  cent,  less  than  normal, 
if  the  other  eye  be  normal.  Germany  accepts  80  per  cent,  of  the  normal 
in  both  eyes.  For  private  pilots  the  standard  varies,  but  the  majority 
require  at  least  two-thirds  normal  vision  or  better  with  correction. 

During  the  present  war  standards  of  visual  acuity  in  several  countries 
have  become  gradually  lowered  owing  to  the  shortage  of  man  power  with 
normal  vision.  Neither  the  United  States  Army  nor  Navy,  however,  has 
yet  lowered  its  visual  standards. 

Peripheral  Vision.  —  Peripheral  vision  is  important,  for  the  flyer 
must  see  on  all  sides  of  him  at  once,  particularly  in  landing,  taking  off,  in 
formation  flying  and  above  all,  when  on  a  military  mission.  Peripheral 
vision  is  also  of  importance  in  night  flying,  as  defects  of  the  color  fields 
are  sometimes  associated  with  night  blindness. 

Visual  fields  are  tested  by  means  of  a  perimeter  or  campimeter  in  the 
great  majority  of  countries.  The  notable  exception  is  Great  Britain, 
which    relies    on     the    confrontation    test.       Berens^    beUeves    that     all 

Vol.  I.  343 


PHYSICAL    REQUIREMENTS 


551 


military  and   passenger-carrying   pilots  should  be   examined  by   the   per- 
imeter on  an  eight  point  field. 

Central  color  vision  is  almost  universally  recognized  as  important  for 
the  flyer.  He  needs  to  detect  colored  lights  on  the  airdrome,  navigating 
lights  on  other  ships,  colored  signal  panels  and  signal  lights  and  what  is 


■■•Mff^ 


\ 


Fig.  I.   Confrontation  test  for  gross  peripheral  visual  held  determination.     (Courtesy, 
The  School  of  Aviation  Medicine,  Randolph  Field,  Texas.) 

more  important,  to  determine  from  the  color  the  character  of  the  terrain 
over  which  he  is  flying  in  case  of  an  emergency  landing.  As  one  ascends, 
the  perspective  of  the  third  dimension  gradually  fades,  and  one  depends 
more  and  more  on  color  vision  to  identify  the  characteristics  of  the 
terrain. 

The  Ishihara  and  Stillings'  plates,  which  are  used  by  many  countries, 
are  delicate  color  tests.     Many  cases  of  partial  color  blindness  are  de- 

VOL.  I.  343 


552  AVIATION   MEDICINE 

tected  by  them  that  are  not  revealed  by  a  simple  test  such  as  the  Holm- 
gren or  Jennings.  It  is  questionable  whether  such  perfect  color  vision  is 
essential  in  flying.  The  Department  of  Commerce  does  not  require  any- 
thing more  than  correct  identification  of  individual  colors. 

A  study  of  partial  red-green  color  blind  cases  by  Cooper^  revealed 
that  only  14  per  cent,  of  partially  color  blind  students  were  able  to  ob- 
tain licenses  as  against  30  per  cent,  of  the  normal.  Wright^^  states: 
"those  of  you,  who  have  flown  along  the  air  lanes  at  night  in  thick 
weather  and  tried  to  distinguish  the  red  flashing  intervals  between  the 
white  beacon  lights  from  those  which  flash  green,  know  how  difficult  a 
matter  it  is  at  best.  The  red  backed  beacons  denote  the  course  of  the 
flight,  and  the  green  backed  beacons  indicate  emergency  landing  fields. 
Any  serious  defect  in  color  vision  would  certainly  make  it  difficult  for  a 
pilot  to  distinguish  the  two  in  rainy  or  foggy  weather.  The  wind  tees, 
which  indicate  the  direction  of  the  wind  at  air  fields,  often  are  lighted 
at  night  by  green  or  red  neon  tubes,  which  are  not  brilHant  shades  of  the 
color  they  are  supposed  to  represent,  and  show  shades,  which  are  difficult 
for  color  blind  persons  to  distinguish  from  other  nearby  lights.  In  the 
daytime,  if  a  forced  landing  is  to  be  made,  an  instantaneous  decision 
must  be  arrived  at  as  to  which  field  is  to  be  used  for  the  attempt  at 
landing.  Inasmuch  as  the  length  of  the  grass,  the  presence  of  holes  or 
irregularities  of  the  ground  are  only  discernible  from  above  by  the  dif- 
ferent shades  of  green  in  a  grass  field,  and  because  the  undertone  of 
brown  in  a  marsh  may  look  similar  to  the  overtone  of  green  to  a  color 
blind  pilot,  who  is  above  this  type  of  ground,  we  believe  that  the  element 
of  danger  is  considerably  increased  by  allowing  color  blind  pilots  to  fly 
passengers." 

Light  Perception.  —  Light  perception  is  now  considered  by  more  and 
more  countries.  Berens^  states  that  night  flying  and  flying  at  dusk 
necessitates  normal  light  perception.  Onfray-"  believes  that  the  visual 
acuity  at  night  should  be  equal,  at  least,  to  rf 0  for  an  illumination  of 
0.0015  lux  after  20  minutes  of  adaptation.  Flynn^^  recently  has  described 
a  clinical  test  for  dark  adaptation  which  he  feels  every  pilot  should  be 
required  to  pass.  It  consumes  but  five  minutes.  It  is  important  also  in 
bringing  out  avitaminosis.  Of  32  pilots,  who  were  demonstrated  to  have 
a  deficiency  in  dark  adaptation,  22  were  successfully  treated  with  10,000 
units  of  vitamin  A  three  times  a  day  for  fourteen  days.  Three  weeks  after 
the  treatment  all  were  retested  and  found  to  be  well  within  normal  limits. 
In  500  cases  tested  6.4  per  cent,  were  found  to  be  deficient  in  vitamin  A. 

Ocular  Muscle  Balance.  —  Ocular  muscle  balance  is  tested  in  the 
United   States   rather   more   carefully   in    the   military   services   than   in 

Vol.  I.  343 


PHYSICAL    REQUIREMENTS 


553 


Fig.  2.    Determination  of  heterophoria.     (Courtesy,  The  School  of  Aviauon  .\kdiciae, 
Randolph  Field,  Texas.) 


commercial  flying.  It  is  also  tested  in  certain  other  countries  but  not 
with  the  same  detail.  Berens''  states  that  latent  heterophoria  often  be- 
comes manifest  or  results  in  diplopia  under  flying  conditions.  It  certainly 
is  a  fact  that  fatigue  and  high  altitude  affect  ocular  muscle  balance.  Fly- 
ing certainly  is  fatiguing.  Heterophoria  is  a  suppressed  condition.  It 
Vol.  I.  343 


554 


AVIATION   MEDICINE 


causes  fatigue  and  results  in  inattention  and  eventually  carelessness.  Poor 
muscle  balance  is  also  a  factor  in  faulty  judgment  of  distance  as  will  be 
seen  later. 

Limits  of  i  diopter  of  hyperphoria  and  a  minimum  of  7  diopters  of 
convergence  and  3  diopters  of  divergence  are  accepted  for  civilian  flyers 
in  this  country;    also  there  must  be  no  diplopia  develop  with  the  head  in 


Fig.  3.    Red  lens  test  for  determination  of  diplopia. 
Medicine,  Randolph  Field,  Texas.) 


(Courtesy,  The  School  of  Aviation 


any  position  except  extreme  angles  on  gazing  at  a  light  20  feet  distant 
with  a  red  glass  in  front  of  one  eye.  The  military  services  also  test  eso- 
phoria  and  exophoria  at  20  feet  and  33  inches,  and  the  angle  of  conver- 
gence also  is  measured.  The  British  use  the  red-green  test  and  the 
Bishop-Harman  apparatus.  Berens«  believes  the  near  point  of  convergence 
IS  important,  and  that  any  near  point  over  80  mm.  should  be  disqualifying. 
Vol.  I.  343 


PHYSICAL    REQUIREMENTS 


555 


Accommodation.  —  Accommodation  is  not  universally  tested,  but  the 
United  States  requires  a  certain  amount  of  accommodation.  The  Army 
and  the  Department  of  Commerce  require  a  minimum  of  2  diopters.  The 
Navy  requires  normal  accommodation  for  age.     The  flyer  must  rapidly 


Fig.  4.    Determination  of  the  near  point  ol  accommodation.     (Courtesy,  The  School  of 
Aviation  Medicine,  Randolph  Field,  Texas.) 

change  his  accommodation  from  that  required  for  reading  his  maps  and 
instrument  board  to  the  relaxation  necessary  for  observing  distant  ob- 

lects. 

Depth  Perception.  —  Judgment  of  distance  is  a  highly  important 
factor.  The  flyer  must  judge  distance,  when  taking  off  or  landing,  from 
the  ground,  trees,  buildings,  telephone  poles,  wires,  other  planes,^  etc.  In 
formation  flying  the  wing  tips  are  but  a  few  feet  apart,  and  a  miscalcula- 
tion of  distance  may  prove  fatal. 

Vol.  I.  343 


556 


AVIATION   MEDICINE 


tG20l0-467J-P0H7-13-38-l0:t0AX12'*)  DEPTH  PERcePTlON  TEST,  SCHOOL  OF    AVIATION 
MEDICINE.  RANDOLPH   FIELD,  TEXAS. 


Fig.  5.  The  Howard  depth  perception  apparatus  in  operation.  The  candidate  is  seated 
20  feet  away  from  the  apparatus  and  looks  at  the  rods  through  the  window  in  the  front. 
The  rods  are  widely  separated,  and  he  endeavors  to  bring  them  parallel.  At  least  three 
trials  are  given,  and  the  average  discrepancy  must  not  be  more  than  30  mm.  The  apparatus 
is  40"  long  and  12"  wide.  The  front  and  rear  ends  are  12"  square.  The  window  in  the 
front  end  is  5"  by  ']\" .  The  rods  are  lof"  high  and  |"  in  diameter.  One  rod  is  fixed, 
and  the  other  moves  forward  or  backward  in  a  slide  groove.  The  entire  apparatus  is  painted 
black  except  the  front  face  of  the  rear  screen,  which  is  painted  white.  (Courtesy,  The 
School  of  Aviation  Medicine,  Randolph  Field,  Texas.) 


Vol.  I.  343 


PHYSICAL   REQUIREMENTS 


557 


Fig.  6.    Formation    flying.      This   calls   for   excellent    depth    perception. 
Photo  Section,  U.  S.  Army  Air  Forces.) 


(Courtesy, 


No  special  tests  of  depth  perception  or  judgment  of  distance  are  re- 
quired by  many  countries  as  they  depend  entirely  on  visual  acuity  and 
normal   muscle  balance.     Some  countries  require  a  test  of  stereoscopic 

Vol.  I.  343 


558  AVIATION   MEDICINE 

vision  with  a  stereoscope.  The  United  States  uses  the  Howard  depth 
perception  apparatus^^  requiring  a  depth  perception  of  not  more  than 
30  mm.  at  20  feet  on  the  average  of  several  trials. 

Stereoscopic  vision  requires  two  eyes,  and  hence  monocular  individuals 
and  those  who  have  markedly  different  vision  in  the  two  eyes  usually 
have  poor  depth  perception.  Poor  ocular  muscle  balance  also  afTects 
depth  perception  adversely.  Clements  of  the  Royal  Air  Force  found  that 
many  students  making  poor  landings  were  doing  this  because  of  defective 
ocular  muscle  balance  and  on  having  this  defect  corrected  87  per  cent,  of 
them  made  satisfactory  landings. 

There  are  a  few  one-eyed  pilots  who  can  judge  distance  fairly  well  and 
are  good  flyers.  There  is  no  question  but  these  men  acquire  a  method  of 
judging  distance  which  the  average  two-eyed  man  does  not  use.  Jarman^'' 
believes  this  to  be  by  means  of  moving  the  head  from  side  to  side.  Having 
lost  the  function  of  binocular  parallax,  he  uses  one  eye  twice  in  an  en- 
deavor to  make  up  for  this  loss  of  normal  function.  Only  old,  experi- 
enced pilots,  however,  should  be  considered  for  waiver  of  such  a  serious 
defect. 

The  time  factor  usually  is  not  considered  in  this  test,  but  it  un- 
doubtedly is  an  important  factor,  as  the  individual  who  judges  distance 
quickly  as  well  as  accurately,  is  safer  than  one  who  judges  it  slowly, 
although  perhaps  as  accurately.  • 

Ocular  Disease.  —  The  eyes  are  inspected  and  the  fundi  examined  for 
ocular  disease  and  abnormalities  and  diseased  conditions  which,  revealed, 
serve  as  a  cause  for  rejection. 

The  Ear,  Nose  and  Throat 

The  ear,  nose  and  throat  are  surveyed  for  defects  and  disease.  It 
has  been  demonstrated  that  under  exposure  to  cold  and  extremes  of 
weather  and  as  a  result  of  fatigue  in  flying  diseased  tonsils,  sinuses  and 
low  grade  ear  infections  are  apt  to  light  up  into  acute  infections.  Such 
should,  therefore,  be  eliminated  at  the  start. 

Requirements  are  much  more  rigid  in  the  military  services  than  in 
civilian  flying.  The  military  services  require  a  practically  perfect  ear, 
nose  and  throat  for  selection.  The  commercial  flyers  are  not  rejected  for 
minor  abnormalities,  and  in  the  private  pilot  gross  defects  sometimes  are 
passed,  such  as  perforated  ear  drums,  for  example.  Middle  ear  conditions 
usually  are  accompanied  by  blocked  or  partially  blocked  Eustachian  tubes, 
and  on  sudden  changes  of  altitude  the  ear  drum  may  be  ruptured,  or  at 
least  its  sudden  retraction  may  cause  excruciating  pain. 

Vol.  I.  343 


PHYSICAL    REQUIREMENTS  559 

Hearing.  —  So  far  as  hearing  is  concerned,  up  until  recently  it  was 
not  considered  very  important.  It  is  well-known  that  the  majority  of  old 
flyers,  old  in  the  sense  of  experience,  have  diminished  hearing.  This  is 
due  to  the  constant  roar  of  the  motor  or  motors.  Protection  is  advised, 
but  flyers  for  some  reason  are  loath  to  wear  it.  The  majority  of  pilots 
flying  open  ships  wear  large  sized  powder  puffs  sewn  into  the  ear  flaps  of 
the  helmets,  but  pilots  of  closed  ships  rarely  wear  any  protection.  In 
closed  ships  the  noise  is  not  nearly  so  severe,  but  even  there  it  is  suffi- 
cient to  damage  hearing. 

Furthermore,  the  increased  use  of  radio  has  made  the  use  of  any  pro- 
tection difficult.  The  pilot  likes  to  keep  his  radio  tuned  in  as  low  as 
possible.  Wright^^  reported  that  a  radio  head  piece  with  cup-shaped  ear 
phones  with  sponge  rubber  inner  surfaces  was  being  worked  out,  and  it  is 
hoped  that  it  or  some  other  device  will  prove  satisfactory. 

The  increased  use  of  radio  necessitates  a  certain  amount  of  hearing 
and  it  is  causing  many  of  the  older  pilots  some  worry  because  they  feel 
they  are  losing  their  hearing.  It  is  a  fact,  however,  that  the  pilots,  who 
are  somewhat  deaf  to  ordinary  tones,  can  still  hear  radio  signals,  the 
tones  required  by  the  radio  not  being  those  to  which  they  are  deaf. 
Good  hearing  then  should  be  required  in  all  pilots  who  are  starting  in 
with  the  idea  of  becoming  commercial  or  military  pilots.  McFarland  and 
associates'^  reported  that  with  increasing  age  there  was  a  gradual  de- 
crease in  acuity  of  hearing  the  higher  frequencies.  He  found  this  decrease 
was  the  same  in  non-flyers. 

Eguilihrium 

This  has  been  a  much  discussed  point.  During  World  War  I  two-thirds 
of  the  articles  written  by  Americans  were  on  the  vestibular  mechanism 
of  the  internal  ear.  The  Barany  tests  were  stressed  and  made  much  of. 
The  French  and  Italians  used  them  largely  also.  The  British  never  did 
have  any  use  for  them.  The  Barany  tests  are  now  largely  in  the  discard 
so  far  as  flying  is  concerned.  In  this  country  they  are  used  only  by  the 
Navy.  The  Army  formeriy  used  the  British  self-balancing  test  but  has 
since  discarded  it.  The  Army  now  has  no  specific  test  of  equilibrium 
as  such.  The  Barany  chair  may  be  used  as  an  emotional  stimulus  in 
cases  of  suspected  neurocirculatory  asthenia  and  doubtful  nervous  sta- 
bility. 

The  Department  of  Commerce  uses  the  self-balancing  test  alone.  It 
consists  in  demonstrating  the  ability  to  stand  on  one  foot  with  the  other 
leg  flexed  at  the  knee,  with  the  eyes  closed,  for  15  seconds.     Three  trials 

Vol.  I.  343 


560 


AVIATION  MEDICINE 


Fig.  7.   The  self-balancing  test  for  equilibrium.     (Courtesy,  The  School  of  Aviation 
Medicine,  Randolph  Field,  Texas.) 


Vol.  I.  343 


PHYSICAL    REQUIREMENTS  561 

are  given.  It  is  then  repeated  on  the  other  foot.  It  is  satisfactory  for  all 
practical  purposes  and  does  away  with  cumbersome  apparatus  that,  at 
best,  was  not  wholly  satisfactory. 

Equilibrium  depends  on  the  sensations  received  from  our  whole  pro- 
prioceptive mechanism.  Its  various  parts  cannot  be  considered  too  in- 
dividually. Vision  is  undoubtedly  the  most  important  factor  in  the  flyer. 
The  tactile  sense  is  largely  non-functioning  in  a  flyer,  but  the  internal  ear, 
visceral  sensations  and  sensations  received  from  the  bones,  joints  and 
muscles  should  be  considered  collectively. 

Equilibrium  has  received  a  new  importance  with  the  advent  of  blind 
flying,  of  which  more  will  be  said  later. 

The  General  Physical  Requirements 

The  general  physical  requirements  are  the  requirements  of  any  thor- 
ough physical  selection.  Sound  heart,  lungs,  kidneys,  a  normal  endocrine 
system,  freedom  from  structural  defects  and  disturbances  of  cardiovascular 
function  and  a  good  medical  history  are  required  and  are  essential.  The 
examination  consists  of  a  thorough  physical  examination. 

Stature.  —  Stature  is  not  so  important  as  it  used  to  be,  but  a  very 
small  or  a  very  large  man  is  not  ideal  because  of  the  resultant  mechanical 
difficulty  in  reaching  or  operating  the  controls.  Men  of  average  stature 
are  preferred  for  fighter  pilots  rather  than  very  tall  men. 

Age.  — -  Age  is  a  disputed  factor,  but  flying  is  still  for  the  younger 
generation.  After  35  to  40  a  conservatism  and  slowness  of  reaction  de- 
velop that  prevent  one  from  becoming  a  high  class  flyer,  if  he  does  not 
learn  until  that  age.  Those,  who  learned  young  and  are  now  between  40 
and  50  years  of  age,  are  in  a  different  class.  They  have  passed  the  most 
difficult  stage  of  their  careers,  namely  training  and  early  experience.  They 
seem  to  continue  to  do  well.  Fighter  and  dive-bomber  pilots  definitely 
are  preferred  of  the  younger  age,  below  28  years.  The  international  reg- 
ulations impose  an  age  limit  of  19  to  45  for  transport  license. 

Structural  Factors.  —  Complete  use  of  the  four  limbs  is  an  international 
requirement.  Loss  of  2  or  3  fingers,  slight  limitations  of  motion  of  the 
ankle,  wrist  or  knee  may  be  permitted,  but  complete  mobility  of  shoulder, 
elbow  and  hip  are  essential  and  only  minor  limitations  of  the  excepted 
joints  permitted.  The  manipulation  of  the  controls,  brakes  and  stabilizer 
require  this  much  as  a  safety  factor.  There  are  a  few  pilots  flying  who 
have  had  one  leg  amputated  below  the  knee,  but  they  all  learned  to  fly 
before  the  amputation  and  are  in  a  special  class,  therefore.  Hernias  in 
the  case  of  transport  or  military  pilots  should  disqualify  until  they  are 

Vol.  I.  343 


562  AVIATION    MEDICINE 

repaired.     Flying  often  is  strenuous,  and  strangulation  a  danger. 

General.  —  The  military,  of  course,  require  freedom  from  organic 
disease  of  the  heart,  lungs,  kidneys,  endocrine  glands  and  digestive 
system.  That  pilots,  who  are  to  carry  passengers,  should  likewise  be 
physically  sound  goes  without  saying.  There  are  a  few  exceptions.  An 
old  arrested  tuberculosis  without  symptoms  may  be  passed  for  commercial 
flying.  Acute  infections  need  be  causes  for  rejection  only  temporarily 
unless  they  leave  manifestly  disqualifying  defects. 

Cardiovascular  System.  —  The  cardiovascular  system  should  not  only 
be  free  from  organic  disease,  but  there  should  be  no  evidence  of  neurocir- 
culatory asthenia.  The  nervous  mechanism  is  under  a  severe  strain  in 
flying  anyway,  and  the  "weak  sister"  drops  by  the  wayside.  More  will 
be  said  of  this  under  the  nervous  system. 

Fatigue,  altitude  and  stress  all  impose  strain  on  the  cardiovascular 
mechanism,  and  hence  it  must  be  normal  to  start  with.  Many  applicants 
come  in  for  their  first  examination  in  a  state  of  apprehension.  High 
pulses  and  blood  pressures  are  encountered  frequently.  The  examiner 
must  eliminate  organic  cardiovascular  disease,  thyroid  disease  and  neuro- 
circulatory asthenia.  Reassurance  and  obtaining  the  confidence  of  the 
applicant  often  will  result  in  the  pulse  and  blood  pressure  returning  to 
reasonable  limits.  The  response  of  the  pulse  to  exercise  and  the  length  of 
time  it  takes  it  to  return  to  its  pre-exercise  rate  are  often  more  important 
than  the  rate  itself.  Any  pulse  that  gives  an  exaggerated  response  to 
exercise  and  is  slow  in  returning  should  be  a  cause  for  rejection,  even  if  no 
organic  disease  is  demonstrable.  Such  an  applicant  probably  is  in  the 
class  of  the  nervously  unstable  and  will  make  poor  flying  material.  Those 
applicants,  who  show  hypertension  on  several  examinations  but  who  have 
no  history  of  hypertension  when  not  under  stress,  rarely  make  good  pilots. 
Many  are  potential  cases  of  essential  hypertension,  and  most  of  them  are 
somewhat  emotionally  unstable. 

Urine  Examination.  —  Nephrosis,  nephritis  and  diabetes  are,  of 
course,  disqualifying  because  of  the  serious  constitutional  effects.  A  urine 
examination  is  manifestly  a  requirement. 

Digestive  System.  —  The  digestive  system  seems  to  be  particularly 
important  in  flyers.  They  have  irregular  hours  and  irregular  meals  with 
food  of  all  kinds  and  at  all  sorts  of  places;  their  bowels  may  of  necessity 
be  irregular  because  of  their  flying  schedules,  and  disturbances  of  the 
gastrointestinal  tract  are  common.  Hence,  the  history  of  any  symptoms 
suggesting  ulcer,  gall  bladder  disturbance,  colitis,  etc.  must  be  gone  into 
with  considerable  care,  and  all  cases  that  seem  to  have  a  definite  gastro- 
intestinal condition  should  be  rejected. 

Vol.  I.  343 


PHYSICAL    REQUIREMENTS  563 

Syphilis.  — ,Syphilis  is,  of  course,  disqualifying.  A  Wassermann  re- 
action is  not  required  for  a  commercial  license  unless  a  history  or  sus- 
picious signs  are  unearthed.  It  would  be  best  if  a  Wassermann  test  was 
required  on  all  prospective  commercial  pilots.  The  military  do  require  it, 
of  course,  as  a  prerequisite  to  commission. 

The  Nervous  System 

The  nervous  system  was  passed  over  superficially  in  the  early  days  of 
flying.  Other  than  examination  by  means  of  a  few  neurological  tests, 
such  as  pupillary  reactions,  station,  knee  jerks,  etc.,  nothing  was  done. 

It  soon  became  apparent  that  the  nervous  system  was  subject  to  great 
wear  and  tear  in  flying,  and  one  of  the  commonest  causes  for  removal 
from  flying  status  was  nervous  instability.  Consequently,  the  develop- 
ment of  a  searching  neuropsychic  examination  took  place.  It  has  reached 
its  highest  peak  in  this  country  in  the  Army  examination.  The  Navy 
and  Department  of  Commerce  also  require  searching  examinations. 

For  practical  purposes  the  following  points  are  all  that  it  is  necessary 
to  cover. 

Neurological  Examination.  —  (i)  Pupillary  abnormalities,  the  cause  of 
which  must,  if  possible,  be  elicited  and  syphilitic  conditions  suspected. 

(2)  Knee  jerks,  with  the  usual  interpretation  of  findings. 

(3)  Station;  both  a  Romberg  and  modified  Romberg  are  done  which 
must  be  satisfactory. 

(4)  Gait;  walking  backward,  forward  and  in  a  circle  with  eyes  open 
and  closed. 

(5)  Tics,  the  presence  of  which  leads  one  to  suspect  an  unstable 
nervous  system. 

(6)  Tremors  of  hands,  eyelids  and  tongue;  if  abnormal,  neurological 
conditions,  hyperthyroidism  and  neurocirculatory  asthenia  must  be  con- 
sidered. 

(7)  Other  motor  abnormalities,  such  as  residual  from  infantile  paralysis. 

(8)  Psychomotor  tension,  the  ability  to  relax  voluntarily.  If  unable 
to  relax,  the  applicant  usually  is  emotionally  unstable  and  will  not  learn 
to  fly  readily. 

(9)  Peripheral  circulatory  flushing,  mottling,  acrocyanosis,  sweating, 
cold  extremities,  the  presence  of  which  suggest  neurocirculatory  asthenia 
or  a  more  serious  nervous  system  derangement. 

Psychic  Examination. — This  part  of  the  examination,  as  Longacre*^ 
so  aptly  states,  "should  begin  when  the  candidate  first  comes  into  view 
and  ends  only  when  he  has  passed  from  sight  and  hearing". 

Vol.  I.  343 


564  AVIATION   MEDICINE 

The  psychic  examination  specifically  includes  a  search  for  a  family 
history  of  epilepsy,  hyperthyroidism,  psychosis  and  psychoneurosis.  The 
family  history  of  any  may  indicate  a  transmitted  nervous  instability. 
Past  personal  history  should  be  searching  and  covers  not  only  the  history 
of  severe  illnesses  and  injuries,  but  a  complete  personality  study  is  made. 
This  covers  childhood  environment  and  reaction  to  discipline,  educational 
history  and  progress,  athletic  life,  social  trends,  somatic  demands,  self- 
expression,  psychomotor  activity,  self-criticism,  temperament,  philosophy 
of  life. 

Longacre^^  has  stated  that  the  purpose  of  this  personality  study  is  to 
study  the  condition  of  the  candidate's  nervous  system.  An  effort  is  made 
to  determine  whether  or  not  there  are  deviations  from  the  normal,  and 
if  so,  whether  or  not  these  deviations  are  sufficient  to  disqualify  him  from 
flying,  to  study  the  candidate's  temperament,  intelligence  and  volition 
and  again  to  determine  deviations  from  normal  for  the  same  reason,  to 
study  the  manner  of  the  candidate's  reaction  to  his  environment  and  to 
unearth  latent  tendencies  which,  under  the  stress  of  flying,  might  become 
accentuated  in  such  a  manner  as  to  render  him  inefficient,  and  to  de- 
termine the  personality  trends,  resistances  and  potentialities. 

During  this  personality  study,  we  may  find  the  following  favorable 
factors:  (a)  Temperament.  —  Cheerful,  stable,  self-reliant,  aggressive, 
modest,  frank,  fond  of  people,  satisfied,  punctilious,  serious,  good  coopera- 
tion in  work  and  in  examination,  good  sportsmanship,  moderate  tension, 
enthusiastic,  adaptable;  (b)  Intelligence.  —  Precise,  penetrating,  sharp, 
alert,  resourceful;  (c)  Volition.  —  Energetic,  quick,  deliberate,  or  moder- 
ately impulsive,  controlled,  good  tenacity  of  purpose. 

We  may  also  find  the  following  unfavorable  factors:  (a)  Tempera- 
ment. —  Depressed,  unstable,  submissive,  pacific,  vain,  withholding,  se- 
cretive, loquacious,  likes  to  be  alone,  hypercritical  of  conditions,  careless, 
frivolous,  poor  cooperation,  irritable,  poor  sportsmanship  (under  adverse 
circumstances,  querulous  and  complaining),  exceedingly  high  tension, 
lost  enthusiasm;  (b)  Intelligence.  —  Vague,  superficial,  dull,  hesitant, 
without  initiative,  untrained;  (c)  Volition.  —  Sluggish,  slow,  recklessly 
impulsive,  restless,  poor  tenacity  of  purpose. 

No  one,  of  course,  will  exhibit  all  favorable  or  all  unfavorable  factors, 
but  the  preponderance  one  way  or  the  other  will  determine  whether  or 
not  he  will  make  a  satisfactory  flyer.  The  importance  of  this  part  of  the 
examination  will  be  realized  when  a  study  is  made  of  the  reasons  given  by 
instructors  why  men  fail  to  learn  to  fly.  Longacre^**  made  such  a  study 
of  the  failures  at  the  Army  primary  flying  school.  He  found  the  following 
reasons  for  failure  as  stated  by  the  instructors:   slow,  mentally  and  phys- 

VoL.  I.  343 


PHYSICAL    REQUIREMENTS  565 

ically;  unable  to  analyze  and  correct  errors;  inconsistent,  erratic  from 
day  to  day;  poor  on  simple  manoeuvres  and  lost  in  acrobatics;  unable 
to  absorb  or  retain  instructions;  poor  in  speed,  distance,  coordination, 
altitudes  and  balance;  no  feel  of  ship;  does  not  realize  his  mistakes  or 
when  he  is  right  and  when  he  is  wrong;  unable  to  sense  slips,  skids,  stalls, 
etc.;  easily  confused;  lacks  initiative  and  aggressiveness;  learns  nothing 
for  himself;  fusses  with  controls;  inattentive  to  instruments,  traffic, 
obstacles,  wind  directions;  jerky  and  rough  on  controls;  kicks  or  rides 
the  rudder;  mechanical  flyer,  and  in  connection  with  that  one  instructor 
very  aptly  completes  the  picture  by  saying  "no  instinctive  performance, 
all  mechanical";  unable  to  coordinate  controls;  headwork  poor;  judg- 
ment poor;  tense,  apprehensive,  nervous  and  excitable;  danger  in  power- 
off;  poor  headwork  on  forced  landing;  excitable  and  blows  up  on 
slightest  provocation;  had  difficulty  because  left-handed;  repeats  his  mis- 
takes over  and  over  again;  forgets  instruction  over  night,  over  the  week- 
end, over  the  Christmas  holidays  and  so  on;  perhaps  too  much  diversified 
interest;  inattentive  to  details;  reaches  his  saturation  point  and  fails  to 
progress;  concentrates  on  flying  the  plane  to  the  exclusion  of  every- 
thing else,  i.e.,  he  excludes  every  factor  in  the  environment,  he  is 
oblivious  to  the  traffic,  the  wind  directions,  lights  and  everything  of 
that  sort;  lets  plane  fly;  never  seems  to  control  it;  hopelessly  unable 
to  fly;  entirely  out  of  his  element;  too  easily  confused;  unable  to 
execute  manoeuvres  requiring  finer  timing  and  coordination;  unable  to 
decide  promptly  and  act  decisively;  unable  to  relax.  He  states  that,  of 
687  failures,  404  were  reported  as  incurably  tense  and  apprehensive. 

Carlson^  reported  that  instructors  "washed  out"  students  frequently 
with  the  following  remarks;  slow  learner,  poor  comprehension,  poor  re- 
tention, poor  headwork,  slow  progress,  unable  to  understand,  forgets 
instructions. 

Longacre^^  further  states  the  following  traits  are  indices  of  such  future 
poor  performance  and  in  a  careful  examination  could  be  unearthed;  "in- 
decisiveness,  inattentiveness,  uncertainty,  indefiniteness,  evasiveness, 
hesitancy,  timidity,  overdeveloped  self-preservative  instinct,  vagueness, 
superficiality,  recklessness,  clumsiness,  awkwardness,  slow  comprehension, 
delayed  or  slow  motor  response,  sluggishness,  poor  retention,  lack  of 
initiative  and  aggressiveness,  self-depreciation,  tenseness,  inability  to 
relax,  being  oversensitive,  being  unduly  introspective,  being  handicapped 
by  an  inability  to  respond  correctly  to  diversified  stimuli,  i.e.,  to  instru- 
ments, ships,  etc.  and  environments  simultaneously." 

We  must,  therefore,  endeavor  to  forecast  the  candidate's  probable 
reaction   to   this  new  experience  of   flying.     Again   to  quote   Longacre^^ 

Vol.  I.  343 


566  AVIATION   MEDICINE 

"the  examination  must  reveal  latent  tendencies  which  under  the  stress  of 
flying  might  become  so  accentuated  as  to  make  him,  the  pilot,  inefficient 
and  lead  to  nervous  and  mental  breakdown;  or  on  the  other  hand,  make 
clear  such  stability  of  organization  as  will  be  proof  against  stresses  ad- 
mittedly exceptional  and  foreign  to  averagg  experience.  It  is  not  conceded 
that  nature  has  at  last  achieved  her  highest  objective  and  in  the  flyer 
produced  a  superman.  It  is,  however,  required  that  he  be  equal  to  the 
requirements  of  any  situation,  usual  or  unusual  and  with  respect  to  the 
unusual,  be  capable  of  the  instantaneous  and  correct  response  demanded 
by  the  emergency." 

Vasomotor  Instability.  —  Examination  for  this  condition  is  conducted 
as  part  of  the  cardiovascular  examination  and  as  part  of  the  neuropsychic 
examination.  The  Army^^  states  that,  if  persistently  present  in  marked 
degree,  it  is  disqualifying  for  pilot  training.  The  following  manifestations 
are  listed;  (i)  rapid  pulse,  (2)  labile  pulse,  (3)  labile  low  blood  pressure, 
(4)  low  Schneider  index,  (5)  cyanotic  extremities,  (6)  cold  clammy  ex- 
tremities, (7)  mottling  of  extremities,  (8)  profuse  axillary  perspiration, 
(9)  palmar  and  plantar  perspiration,  (10)  tremors  of  extended  hands, 
(11)  tremors  of  closed  eyelids,  (12)  tremulousness  of  muscles  of  face  and 
lips,   (13)  tremulousness  of  speech. 

In  each  case  the  flight  surgeon  is  cautioned  to  evaluate  any  of  the 
signs  of  vasomotor  instability  with  all  the  other  findings  in  the  complete 
examination  to  determine  the  individual's  ability  to  withstand  the  signs 
of  military  aviation. 

Reaction  Time  and  Flying  Aptitude 

Reaction  time  ,has  always  been  considered  an  important  factor  in 
flying,  and  various  attempts  have  been  made  to  devise  a  satisfactory  ap- 
paratus. During  World  War  I  simple  reaction  times  were  tested,  but  they 
have  been  discarded  nearly  universally  as  being  worthless.  It  was  found 
that  the  promptness  with  which  an  individual  might  tap  a  telegraph  key  in 
response  to  a  stimulus  of  a  light,  a  bell  or  an  electrode  on  the  hand  was 
no  indication  of  how  he  might  respond  with  a  complicated  arm  and  leg 
movement  under  the  proper  stimulus  in  the  air. 

The  Ruggles  orientator  was  devised  in  this  country  and  was  used 
considerably.  It  consisted  of  the  cockpit  of  an  airplane  suspended  in 
three  concentric  rings  controlled  by  motors  and  governed  either  from  the 
cockpit  or  the  ground.  The  candidate  could  be  placed  in  every  conceiv- 
able position  with  relation  to  the  horizon  and  put  through  any  rotary 
motion.    The  disadvantage  of  the  apparatus  was  that  the  results  of  train- 

VOL.  I.  343  ^ 


REACTION   TIME  AND   FLYING  APTITUDE 


567 


ing  in  it  were  purely  a  matter  of  personal  opinion  of  the  operator.     There 
was  no  graphic  record,  and  it  has  been  discarded. 

The  Reid  reaction  apparatus  is  an  improvement  in  that  it  has  a 
graphic  record  of  the  candidate's  performance.  It  consists  of  the  cockpit 
of  a  plane   fitted   with   seat,   stick  and   rudder  bar.     On   the  instrument 


Fig.  8.   The  serial  reaction  apparatus  in  operation.     (Courtesy,  The  Sehuol  of  x\viation 
Medicine,  Randolph  Field,  Texas.) 


board  are  two  rows  of  lights,  one  for  the  stick  and  one  for  the  rudder. 
When  in  an  extreme  position  all  the  lights  are  lighted.  They  gradually 
go  out  as  the  controls  approach  neutral.  Whenever  the  controls  are  ofif 
neutral,  a  recording  pen  continues  writing  until  the  neutral  point  is 
reached  and  maintained.  A  chronometer  measures  the  length  of  time  in 
fractions  of  a  second  that  the  controls  are  off  neutral. 
Vol.  I.  343 


568  AVIATION   MEDICINE 

The  test,  after  a  practice  period,  consists  in  having  the  controls  placed 
in  an  extreme  position.  The  chronograph  starts,  the  pen  writes,  and  the 
length  of  time  it  takes  to  neutralize  the  controls  is  recorded  graphically. 
Ten  tests  of  rudder,  lo  of  stick  and  20  of  combined  stick  and  rudder  are 
so  made.  Then,  while  one  test  is  being  made,  a  klaxon  horn  back  of  the 
candidate  is  blown  suddenly,  and  the  effect  of  the  emotional  disturbance 
in  prolonging  reaction  time  is  noted  and  also  in  succeeding  tests  the  length 
of  time  it  takes  to  come  back  to  his  average  performance  before  the  horn 
was  blown. 

The  average  reaction  time  is  figured  and  the  candidate  rated  accord- 
ingly. The  British  claim  remarkable  results  with  it.  They  state  that 
there  is  an  80  to  90  per  cent,  correlation  between  the  results  of  the  test 
and  the  actual  flying  record  in  the  schools  of  instruction. 

The  slower  the  reaction  time,  the  poorer  the  flyer,  as  a  rule,  and  any- 
one whose  reaction  time  is  below  4  seconds  is  not  considered  worth  train- 
ing, and  those  who  cannot  do  better  than  3.5  seconds  probably  will  make 
only  mediocre  pilots  at  best. 

A  serial  reaction  apparatus  was  devised  in  1934  by  Mashburn  and 
Constable  and  reported  by  Mashburn  as  an  automatic  apparatus  designed 
to  present  a  continuous  series  of  stimuli-^  The  responses  to  the  signals 
are  made  by  a  coordinated  movement  of  a  series  of  controls  operated  by 
the  hands  and  feet.  The  correct  response  to  a  set  of  signals  automatically 
sets  up  the  succeeding  signals  until  the  whole  series  is  completed.  A 
reactor's  score  is  the  total  time  required  to  run  through  the  complete 
series. 

This  test  still  is  being  used  at  certain  reception  centers  in  the  Army 
in  conjunction  with  five  other  psychomotor  tests  in  an  effort  to  find  a 
group  of  tests  which  will  have  a  high  correlation  rate  with  the  successful 
completion  of  flying  training. 

For  commercial  flying  no  such  complicated  tests  and  no  expensive 
apparatus  as  those  just  described  can  be  used.  We  must  depend  on  the 
neuropsychic  examination,  already  outlined.  With  careful  examinations 
and  with  particular  lookout  for  the  factors,  enumerated  by  Longacre  as 
indicating  poor  aptitude,  we  can  arrive  at  fairly  satisfactory  results. 

The  Army  has  adopted  an  adaptability  rating  for  military  aeronautics 
aptitude^^.  This  is  based  on  an  even  more  detailed  personality  study 
than  the  one  outlined  under  the  nervous  system.  The  following  factors 
are  studied  and  a  maximum  rate  for  each  factor  is  reckoned  as  follows 
on  the  next  page: 


Vol.  I.  343 


REACTION  TIME  AND   FLYING  APTITUDE  569 


Family  history 

05 

Environment 

05 

Morphology 

10 

Intelligence 

60 

Achievement 

20 

Psychomotor  activity 

20 

Emotionality 

35 

Somatic  demands 

25 

Sociality 

15 

Philosophy  of  life 

05 

Total 

200 

160  points  are  required  to  qualify.  An  unsatisfactory  adaptability  rating 
must  be  supported  by  at  least  one  of  the  following  18  reasons:  (i)  his- 
tory of  multiple,  2  or  more,  instances  of  mental  disturbances  in  the  im- 
mediate family  (father,  mother  and  siblings) ;  (2)  intelligence  is  considered 
below  the  required  standard  because  of  (a)  many  failures  in  the  grades 
and  high  school  requiring  extra  months  or  years  to  complete  high  school, 
(b)  inability  to  accomplish  two  years  of  college  work  because  of  many 
academic  failures,  (c)  complete  lack  of  accomplishment  to  date  and 
failure  to  take  advantage  of  opportunities  (school  and  work),  (d)  specific 
instances  of  applicant's  behavior  indicating  questionable  intelligence. 
Record  must  be  made  of  evidence  demonstrating  poor  judgment,  poor 
comprehension,  poor  memory,  poor  attention,  poor  learning  or  other 
faulty  intellectual  operations.  These  must  be  so  obvious  that  they  out- 
weigh any  educational  attainments;  (3)  a  history  of  somnambulism; 
(4)  a  history  of  stammering  or  presence  of  a  tic;  (5)  a  history  of 
migraine  or  migraine  type  of  headache;  (6)  a  history  of  amnesia,  (psycho- 
genic) ;  (7)  a  history  of  skull  fracture  or  severe  concussion  with  per- 
sistent symptoms,  any  period  of  unconsciousness  of  2  hours  or  longer; 
(8)  a  history  of  epilepsy  or  convulsions;  (9)  a  history  of  fainting  due  to 
inadequate  cause  subsequent  to  age   12,  the  only  adequate  causes  being 

(a)  pain  following  a  severe  injury,  (b)  during  convalescence  from  an 
acute  illness,  (c)  moderate  to  severe  loss  of  blood;  (10)  persistent  in- 
somnia (anxiety);  (11)  obsessions  or  phobias  which  motivate  conduct; 
(12)  instability  manifest  by  combinations  of  the  following,  one  or  even 
two    not    necessarily    disqualifying;      (a)  convulsions    in    minor    illness, 

(b)  prolonged    enuresis;     if    to    present    time,    it    alone    is    disqualifying, 

(c)  frequent  headaches,  (d)  multiple  histories  of  momentary  unconscious- 
ness in  minor  injuries,  (e)  pavor  nocturnus  (anxiety),  (f)  mtld  insomnia 
(anxiety),    (g)  nail    biting,    (h)  mannerisms,    (i)  excessive    tobacco,    (j)  a 

Vol.  I.  343 


570  AVIATION    MEDICINE 

low  Schneider  index,  (k)  tenseness;  (13)  excessive  alcohol  or  criminal 
history;  (14)  any  major  psychosis;  (15)  any  minor  psychosis  (psycho- 
neurosis);  (16)  any  constitutional  psychopathic  state;  (17)  the  following 
personality  trends,  if  present  to  a  considerable  degree,  seclusive,  overac- 
tive, depressive,  suspicious,  egotistical,  irritable,  sexually  abnormal  and 
criminalistic;    (18)  any  neurological  disqualification. 

Periodicity  of  Examinations 

All  countries  require  sortie  sort  of  physical  examinations  for  their 
military  air  forces,  and  most  countries  require  stringent  examinations  as 
already  described  for  both  military  and  civilian  pilots.  The  United  States 
and  many  Other  countries  require  a  satisfactory  physical  examination  for 
flying  before  an  individual  may  solo  in  licensed  aircraft.  It  is  a  universal 
practice  to  require  re-examinations  of  licensed  pilots  at  stated  intervals. 
All  civil  pilots  are  examined  once  a  year.  Air-line  pilots  are  examined  at 
least  twice  a  year.  All  pilots  must  be  re-examined  following  an  accident 
before  resuming  flying.  The  United  States  requires  its  military  pilots  to 
be  re-examined  twice  a  year.  The  mid-year  examination  is  only  a  check 
of  the  more  important  points.  The  annual  examination  is  complete. 
Following  accidents  or  serious  illness,  an  examination  is  required  also 
before  resuming  flying.  Air-line  pilots  in  the  United  States  are  examined 
at  least  twice  annually  and  other  pilots  annually. 

Physical  Defect  and  Flying  Ability 

Much  has  been  said  already  about  the  necessity  of  a  normal  physical 
makeup  for  flying  and  how  the  examinations  for  selection  of  the  flyer 
have  grown  more  stringent.  It  may  be  well  at  this  point  to  consider 
what  happens  to  the  flyer  who  is  not  physically  sound,  particularly  in 
his  training  period. 

Bauer  and  Cooper^  studied  the  records  of  9,000  students  without  prev- 
ious experience  and  the  records  of  about  2,000  accidents  in  trained  flyers. 
Later  Cooper^"  carried  it  further  to  cover  about  30,000  students  and  over 
4,000  accidents. 

In  the  first  study  the  records  of  all  student  pilots  licensed  by  the  U.  S. 
Department  of  Commerce,  who  had  had  a  year  or  more  since  the  issuance 
of  their  student  permits  in  which  to  obtain  a  higher  grade  of  license, 
were  studied.  No  student  was  included  who  had  had  previous  experience 
in  flying.  The  students  were  classified  according  to  their  physical  con- 
dition.    The  study  showed  that  of  those  with  no  defects,  35.4  per  cent. 

Vol.  I.  343  » 


PHYSICAL   DEFECT  AND   FLYING   ABILITY  571 

obtained  a  private  license  or  better  in  a  year;  those  with  minor  defects, 
30.3  per  cent,  advanced;  those  with  major  defects,  18.5  per  cent,  ad- 
vanced and  of  those  with  disquaUfying  defects,  only  12.5  per  cent,  ad- 
vanced. In  other  words,  as  the  defect  increased  in  magnitude,  the  less 
chance  the  individual  had  of  learning  to  fly. 

CooperV  study  of  30,000  students  showed  similar  but  more  marked 
discrepancies  between  the  groups.  In  this  study  the  normal  group 
showed  a  progress  rate  of  30.5  per  cent.;  the  minor  defect  group,  17 
per  cent.;  the  major  defect  group,  14.7  per  cent,  and  the  disqualified 
group,  4.1  per  cent.  He  found  also  as  to  the  group  with  disqualifying 
defects  that,  all  told,  286  permits  had  been  issued  to  students  with  dis- 
qualifying defects,  and  of  these  286  only  6  at  the  time  of  the  study  held  a 
license  of  any  sort.  In  other  words,  if  regulations  did  not  stop  their 
flying,  nature  did. 

Cooper^"  went  a  step  further  in  this  latter  study  and  broke  down  the 
large  groups  into  classes  of  defects.  As  would  be  expected,  he  found  that 
some  defects  were  more  serious  than  others.  For  example,  in  the  group 
of  so-called  minor  defects  he  found  that  mild  structural  defects  and  minor 
defects  of  hearing  showed  a  progress  rate  of  21.5  per  cent,  as  against  17 
per  cent,  for  the  group  as  a  whole  and  30.5  per  cent,  for  the  normals. 
Moderate  defects  of  color  vision  showed  a  progress  rate  of  only  14  per 
cent.,  thus  bearing  out  Wright's  contention  already  mentioned.  Those 
with  high  pulses  and  blood  pressures  had  a  progress  rate  of  only  8  per 
cent.  This  is  in  line  with  Longacre's  findings  that  nervousness  and 
apprehension  are  common  causes  of  failure  in  learning  to  fly.  In  the 
group  of  major  defects  defective  vision  showed  a  progress  rate  of  21.5  per 
cent,  as' against  14.7  per  cent,  for  the  group  as  a  whole  and  30.5  per  cent, 
for  the  normals;  general  physical  defects,  a  rate  of  5.8  per  cent.;  ocular 
muscle  imbalance,  a  rate  of  4.1  per  cent.;  inferior  neuropsychic  makeup  a 
rate  of  3.5  per  cent.,  again  emphasizing  the  importance  of  a  sound  nerv- 
ous system;  while  structural  defects  and  defective  equilibrium  showed 
a  rate  of  o. 

All  this  proves  rather  conclusively  that  physical  condition  and  the 
ability  to  learn  to  fly  are  closely  related.  The  greater  the  physical  defect, 
the  poorer  the  chance  of  becoming  a  flyer. 

The  study  of  accidents  by  Bauer  and  Cooper^  showed  that  in  1928  the 
accident  rate  in  normal  pilots  was  13.6  per  cent.;  in  pilots  with  some 
physical  defect,  the  rate  was  18.2  per  cent.  In  1929  the  rate  for  the 
normal  group  was  12.3  per  cent,  and  for  the  defective  group  18. 2  per  cent. 
Figured  in  another  way,  in  1928  the  percentage  of  normal  pilots  who  had 
accidents  was  10.5  per  cent,  and  the  percentage  of  defective  pilots  who 

Vol.  I.  343 


572  AVIATION   MEDICINE 

had  accidents  was  18.5  per  cent.  In  1929  the  figures  were  10.6  for  the 
normal  and  15.6  for  the  defective.  The  normal  pilots  showed  a  fatality 
rate  in  accidents  of  1.55  per  cent,  and  the  defectives  a  rate  of  2.36  per 
cent. 

Cooper'"  studied  4,227  accidents  and  considered  the  transport,  the 
limited  commercial  and  the  private  pilots  separately.  He  found  the 
private  pilots,  who  had  physical  defects,  had  accidents  33^  per  cent, 
more  often  than  the  normal,  and  the  fatal  accidents  were  66f  per 
cent,  more  numerous  among  the  defective  than  among  the  normal.  In 
the  limited  commercial  grade  the  figures  were  the  same  as  for  the  private 
pilots  for  accidents,  and  the  fatal  accidents  were  50  per  cent,  greater 
among  the  defectives  than  among  the  normal. 

In  the  transport  grade  the  accident  rate  in  the  physically  defective 
group  was  50  per  cent,  greater,  and  the  fatal  accidents  were  the  same  in 
both  groups.  Cooper  explains  the  latter  fact  by  stating  that  transport 
pilots  in  view  of  their  greater  experience  are  more  apt  to  get  out  of  serious 
situations  with  less  damage. 

The  work  by  Bauer  and  Cooper  has  been  criticized  as  not  being  borne 
out  by  facts.  However,  Herbolsheimer'*  has  just  made  a  study  of  300 
unselected  aviation  accidents  and  found  that  the  accident  rate  in  pilots 
with  physical  impairments  was  one-third  greater  than  the  ratio  of  physi- 
cally defective  pilots  certificated.  This  study  was  on  reported  civil  air  acci- 
dents in  1941. 

As  a  check  the  last  100  accidents  reported  up  to  August  1942  were 
analyzed,  and  the  figures  were  in  close  agreement  with  the  1941  figures. 
From  the  results  of  the  study  Herbolsheimer  states:  "It  appears  safe  to 
conclude  that  pilots  with  physical  impairments  can  reasonably  be  ex- 
pected to  be  involved  in  aviation  accidents  more  frequently  than  persons 
with  no  impairments". 

These  figures  are  not  radically  difi'erent  from  those  of  Cooper,  who 
found  the  rate  of  accidents  in  various  types  of  pilots  was  from  33  to  50 
per  cent,  greater  in  the  group  with  physical  impairments. 

It  has  been  alleged  that  flying  experience  is  a  greater  deterrent  of 
accidents  than  physical  condition.  No  one  denies  that  the  experienced 
pilot  is  less  prone  to  accidents,  but  it  must  be  remembered  that  aviation 
accidents  are  apt  to  be  fatal,  and  hence,  as  Herbolsheimer  states,  "there 
are  few  'repeaters'",  so  that  those  prone  to  accidents  are  eliminated. 
Furthermore,  in  any  study  of  experienced  pilots  the  type  of  flying  done, 
type  of  aircraft  flown,  whether  local  hops  or  cross  country,  blind  flying, 
weather  conditions,  etc.,  must  be  known,  as  they  all  aff^ect  the  pilot's 
"accident  exposure". 

Vol.  I.  343 


THE   EFFECTS  OF   HIGH   ALTITUDE 


573 


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'"  MM  H9  PRESSURE                                                           1 

Fig.  9.    Alveolar  air  pressures.      (From  Bauer,  Aviation  Medicine,  courtesy,  Williams 
and  Wilkins  Co.) 


The  Effects  of  High  Altitude 

Military  flying  is  being  done  at  increasingly  high  altitudes,  30,000  to 
40,000  feet.  In  commercial  flying,  except  when  flying  over  mountamous 
country,  8,000  feet  is  about  the  limit  except  in  the  so-called  "stratosphere 
planes".  In  crossing  the  Rocky  Mountains  altitudes  of  10,000  to  14,000 
feet  may  be  reached.     Stratosphere  planes  are  now  in  use  on  some  of  the 

Vol.  I.  343 


574  AVIATION    MEDICINE 

air-lines.  They  are  really  substratosphere  planes  and  not  stratosphere. 
They  fly  at  about  20,000  feet.  They  have  a  hermetically  sealed  cabin  in 
which  the  atmosphere  is  kept  at  a  level  which  does  not  require  supple- 
mentary oxygen.  Recently  much  has  been  heard  about  building  planes 
that  can  fly  in  the  stratosphere,  above  50,000  feet,  in  order  to  take  ad- 
vantage of  the  wind  direction  and  speed  at  that  height. 

In  this  connection  it  must  be  borne  in  mind  that  the  average  unaccli- 
matized  person  becomes  unconscious  without  oxygen  at  about  25,000  feet. 
With  oxygen  he  may  go  considerably  higher.  What  the  exact  limit  is 
varies  probably  with  the  individual,  his  physical  condition  and  weather 
conditions.  However,  it  is  somewhere  near  47,000  feet.  At  this  level, 
or  near  it,  the  pressure  of  oxygen,  even  when  the  individual  is  breathing 
pure  oxygen  from  a  supplementary  supply,  is  too  low  to  sustain  life,  and 
the  individual  dies. 

The  early  effects  of  oxygen  want  are  evidenced  by  an  increased 
volume  of  respiration  per  minute.  The  pulse  accelerates,  possibly  in  an 
effort  at  compensation,  but  probably  chiefly  as  a  sign  of  distress.  The 
blood  pressure  may  remain  level  until  just  before  unconsciousness,  when 
there  may  be  a  gradual  rise  of  the  systolic  pressure  and  a  gradual  fall 
of  the  diastolic.  In  some  cases  either  the  systolic  or  diastolic  pressure 
may  fall  suddenly,  causing  circulatory  failure  with  fainting. 

The  effects  of  oxygen  want  on  the  brain  are  evidenced  first  by  a 
feeling  of  exhilaration.  Then  there  is  a  loss  of  attention,  particularly  a 
restriction  of  the  field  of  attention,  and  an  inability  to  coordinate  the 
finer  muscular  movements.  This  may  be  seen  experimentally  in  the 
handwriting  of  an  individual.  Finally,  judgment  is  lost.  Vision  and 
hearing  do  not  diminish  until  just  before  unconsciousness.  The  effects 
develop  insidiously,  and  frequently  they  are  compared  to  the  effects  of 
alcohol.  Unconsciousness  may  ensue  without  the  individual  being  at  all 
aware  of  anything  wrong. 

As  one  ascends  into  higher  altitudes,  the  barometric  pressure  gradu- 
ally falls,  and  the  oxygen  percentage  remains  constant.  The  oxygen 
pressure  in  the  atmosphere  is  determined  by  the  formula: 

Oxygen  percentage  X  barometric  pressure. 

For  example,  at  sea  level,  the  oxygen  pressure  is  760  mm.  X  0.21  = 
159-1-  mm.  Hg. 

Alveolar  oxygen  pressure  determines  the  amount  of  oxygen  absorbed 
into  the  blood.  Alveolar  oxygen  pressure  is  determined  by  deducting 
the  pressure  of  water  vapor  accumulated  in  inspired  air  (47  mm.  at  any 
level)   and  multiplying   the  remainder  by  the  oxygen  percentage.     The 

Vol.  I.  343 


THE    EFFECTS  OF   HIGH   ALTITUDE  575 

oxygen  percentage  in  the  alveoli,  however,  is  not  0.21  but  approximately 
0.145  per  cent,  as  it  has  become  diluted  by  the  time  it  reaches  the  al- 
veoli.    Hence  at  sea  level  the  alveolar  oxygen  pressure  is 

760  -  47  =  713  X  .145  =  103+  mm. 

As  one  ascends,  the  alveolar  oxygen  pressure  falls.  If  one  adds  sup- 
plementary oxygen  to  the  inspired  air,  he  increases  the  oxygen  percentage 
and  can,  therefore,  increase  the  alveolar  oxygen  pressure.  This,  as  will 
be  seen,  is  true  only  up  to  a  certain  point. 

The  pressure  of  oxygen  is  what  man  depends  upon  for  life.  At  47,000 
feet  the  barometric  pressure  is  100  mm.  of  mercury  and  47  mm.  of  water 
vapor  accumulates  in  inspired  air  before  it  reaches  the  alveoli  of  the  lungs. 
This  must  be  deducted  from  the  atmospheric  pressure.  This  leaves  us 
53  mm.  of  available  atmospheric  pressure  in  the  alveoli.  From  this  must 
also  be  deducted  the  carbon  dioxide  pressure.  There  is  no  known  method 
of  breathing  supplementary  oxygen  that  prevents  dilution  by  outside  air, 
and  hence  this  less  than  53  mm.  of  possible  O2  pressure  is  reduced  still 
further.  Forty  mm.  of  pressure  in  the  alveoli  is  about  the  minimum  at 
which  man  can  exist  for  more  than  a  few  minutes.  Even  then,  the  blood 
is  somewhat  venous  and  the  individual  suffering  from  extreme  oxygen 
want.  In  addition  the  carbon  dioxide  pressure  has  fallen,  due  to  the  in- 
creased ventilation  of  the  lungs,  and  this  fall  in  carbon  dioxide  pressure 
decreases  the  dissociation  of  oxygen  from  the  hemoglobin  in  the  tissues. 
Hence,  somewhere  about  47,000  feet  is  the  absolute  limit  for  man  even 
when  breathing  pure  oxygen. 

From  10,000  feet  to  about  34,000  feet  the  use  of  supplementary  oxygen 
in  gradually  increasing  percentages  will  restore  the  aviator  to  sea-level 
conditions.  At  33,000  feet  he  needs  100  per  cent,  oxygen.  From  then  on 
up  even  with  100  per  cent,  he  again  suffers  from  increasing  oxygen  want, 
due  to  the  diminished  partial  pressure  of  oxygen  available.  It  has  been 
estimated  that  a  man  at  a  little  over  40,000  feet  breathing  pure  oxygen 
is  in  the  same  condition  as  a  man  at  18,000  feet  without  oxygen,  and 
somewhere  around  47,000  feet  he  will  die  even  though  breathing  100 
per  cent,  oxygen. 

The  flights  in  a  balloon  to  the  stratosphere  by  Piccard  were  accom- 
plished by  the  observers  being  sealed  in  a  metal  ball  in  which  the  atmos- 
pheric pressure  was  kept  up  to  a  point  compatible  with  life.  In  flights  of 
airplanes  to  this  level  the  cabin  was  sealed  hermetically  and  the  pressure 
within  the  cabin  artificially  kept  at  a  level  compatible  with  life  as  well  as 
a  means  provided  for  elimination  of  carbon  dioxide,  as  an  excess  of  the 
latter    is    as  bad   as    too    little.      In    pressure    cabins    the    atmosphere   is 

Vol.  I.  343 


576 


AVIATION   MEDICINE 


kept  at  a  level  of  8,000  feet.  At  altitudes  of  40,000  or  more  feet,  if  a 
leak  ensues,  not  only  will  acute  oxygen  want  develop,  but  unconscious- 
ness will  ensue  rapidly  and  air  "bends"  are  apt  to  occur. 

On  repeated  flights  to  high  altitudes  above  10,000  feet  oxygen  should 
be  used.  On  any  flight  above  12,000  feet  it  should  be  used.  No  flyer 
can  perform  his  mission  safely  and  efficiently  at  high  altitudes  without 
oxygen.  Barach  states  that  impairment  of  reason,  memory  and  judgment 
takes  place  at  altitudes  as  low  as  12,000  feet^ 

Gaseous  oxygen  is  the  type  commonly  used.  It  is  fed  to  the  pilot 
through  a  face  mask  of  the  B.L.B.  or  similar  type''. 


Fig.  10.     The  Boothby-Lovelace-Bulbullian  (B.L.B.)  nasal  oxygen  mask. 
Walter  M.  Boothby  and  the  Bruce  Publishing  Company.) 


(Courtesy 


Aero  Embolism  and  Emphysema 


At  levels  above  25,000  feet  we  encounter  not  only  the  effects  of  oxygen 
want  but  the  effects  of  greatly  lowered  barometric  pressure.  With  rapid 
ascents  through  these  high  altitudes  nitrogen  is  given  off  in  gaseous  form 
into  the  blood  and  tissues.  If  the  gaseous  bubbles  are  in  the  blood, 
they  may  form  air  emboli.  If  they  penetrate  the  tissues  emphysema 
results.  The  condition  is  the  same  as  what  has  long  been  known  as 
caisson  disease  or  the  "bends".  The  condition  may  be  sufficient  to  cause 
discomfort,  actual  distress  or  even  total  disability.     It  occurs  frequently 

Vol.  I.  343 


EFFECTS  OF  HIGH  SPEED  577 

at  levels  between  30,000  and  40,000  feet.     Paralysis  may  result  from  air 
embolism  to  the  spinal  cord. 

Behnke^  states  that  "bends"  will  develop  between  25,000  and  28,000 
feet  without  preoxygenation.  By  this  is  meant  breathing  100  per  cent, 
oxygen  prior  to  the  take-off.  He  found  that  with  45  minutes  of  pre- 
oxygenation bends  did  not  develop  until  30,000  feet  were  reached;  with 
go  minutes,  not  until  34,000  feet;  with  three  hours,  not  until  37,000  feet 
and  with  five  hours,  not  until  40,0000  feet.  He  found  also  that  using  a 
mixture  of  oxygen  and  helium  instead  of  pure  oxygen  shortened  the  time 
necessary  to  accomplish  the  same  end.  For  example  90  minutes  of 
breathing  the  oxygen-helium  mixture  was  equivalent  to  5  hours  of  pure 
oxygen.  Behnke  found  also  that  the  younger  group  of  pilots  was  far  less 
susceptible  to  aero  embolism  than  the  older  group.  He  recommends  pre- 
flight  tests  for  selection  of  those  to  do  high  altitude  flying. 

Effects  of  High  Speed 

High  speed  in  flying  is  becoming  more  and  more  common.  Passenger 
airplanes  now  frequently  travel  at  200  or  more  miles  per  hour.  Such  a 
speed,  however,  is  not  particularly  dangerous.  The  speed  planes,  however, 
flying  300  or  more  miles  per  hour  are  a  different  matter.  Dive-bombing 
in  which  the  plane  attains  500  miles  per  hour  before  the  pull-out  is 
serious. 

Straight  ahead  speeds  are  far  less  dangerous  than  speed  on  turns, 
because  the  acceleration  is  gradual,  and  there  is  no  change  of  direction. 
In  turning,  however,  there  is  danger  of  unconsciousness.  Even  turning 
sharply  at  200  miles  an  hour  may  cause  everything  to  become  blotted  out 
for  the  flyer.  This  usually  is  transitory,  and  the  flyer  promptly  recovers. 
Sometimes  the  "blotting  out"  persists  for  several  seconds.  One  flyer, 
who  pulled  his  ship  up  in  a  test  at  190  miles  an  hour,  states  that  every- 
thing remained  black  for  45  seconds.  One  Army  officer  did  not  fully 
recover  his  vision  for  several  hours.  Garsaux'*  in  experiments  on  dogs 
rotated  the  animals  on  a  wheel  at  speeds  varying  from  four  to  six  turns 
per  second.  Some  of  the  dogs  showed  actual  brain  damage  due  to  the 
pressure  of  the  brain  against  the  skull.  Autopsies  showed  an  anemia  of 
the  brain  and  an  engorgement  of  the  vessels  of  the  abdominal  area. 

In  dive-bombing  the  pull  of  centrifugal  force  on  change  of  direction  at 
about  500  miles  per  hour  amounts  to  5  or  more  G's.  i  G  is  equal  to  the 
pull  of  gravity,  namely,  the  pull  to  which  we  are  accustomed  and  which 
keeps  us  from  falling  off  the  earth.  When  this  pull  is  increased,  we 
feel  the  effects.     At  a  pull  of  5   G's  muscular  power  is  overcome,  and 

Vol.  I.  343 


578  AVIATION   MEDICINE 

breathing  becomes  almost  impossible.  The  blood  is  drained  away  from 
the  upper  part  of  the  body,  and  unconsciousness  ensues.  There  may  be, 
according  to  some,  a  factor  of  vasomotor  relaxation  in  addition  to  the 
pull  of  centrifugal  force. 

The  exact  point  of  unconsciousness  depends  somewhat  on  individual 
tolerance,  but  it  occurs  between  6  to  8  G's.  There  is  a  fall  in  blood  pres- 
sure in  the  upper  half  of  the  body  and  an  increase  in  the  lower  half  as 
would  be  expected.  Fulton^-^  states  that  at  7  G's  a  man  weighing  180  lbs. 
would  weigh  1,260  lbs.,  the  weight  of  the  hydrostatic  column  of  blood  on 
the  arterial  side  would  be  more  than  the  heart  could  cope  with,  and  the 
venous  blood  would  fail  to  return  from  below  the  cardiac  level. 

All  these  remarks  pertain  to  positive  acceleration,  which  is  the  common 
condition  met  in  flying.  Negative  accelerations  are  met  in  certain  acro- 
batic manoeuvres.  Here  we  find  the  reverse,  the  blood  being  drawn  to 
the  upper  part  of  the  body  with  resulting  seeing  "red"  instead  of  "black", 
with  cerebral  congestion,  conjunctival  and  even  cerebral  hemorrhages 
being  a  possibility.  Armstrong-  states  that  at  4I  G,  the  highest  negative 
acceleration  studied  in  man,  there  is  mental  confusion,  persisting  for 
several  hours,  accompanied  by  severe  throbbing  headache.  The  face  is 
congested,  petechial  hemorrhages  result  in  the  skin  and  conjunctivae,  and 
subcutaneous  ecchymoses  may  remain  for  hours  or  days. 

Prevention  of  the  effects  of  positive  accelerations  may  be  obtained  in 
part  by  (i)  the  pilot  wearing  an  inflatable  abdominal  belt  exerting  suffi- 
cient pressure  to  prevent  pulling  of  the  blood  to  the  lower  half  of  the 
body,  (2)  placing  the  pilot  in  a  crouching  posture,  so  as  to  bring  the  pull 
of  centrifugal  force  more  transversely  rather  than  from  head  to  feet  and 
(3)  by  having  liim  yell  at  the  top  of  his  lungs,  thereby  fixing  his  dia- 
phragm and  causing  some  cerebral  congestion. 

Effects  of  Cold  and  Wind 

Considerable  work  has  been  done  recently  on  the  effects  of  cold  in 
flying.  We  know  that  during  the  first  mile  of  ascent  the  temperature  falls 
10°  F.  in  every  540  feet  of  ascent.  From  14,000  to  16,000  feet  there  is  a 
fall  of  1°  F.  in  every  360  feet  of  ascent.  From  23,000  to  29,000  feet  there 
is  a  fall  of  i°  F.  in  every  188  feet  of  ascent.  Above  35,000  feet  is  the 
zone  of  constant  temperature,  -67°  F.  below  zero. 

Schneider^*  states  that  in  flight  cold  increases  by  stages.  First  there  is 
a  sensation  of  chilling,  a  development  of  goose-pimples  and  pallor;  if 
there  is  not  sufficient  protection,  the  chilling  accentuates,  there  is  a  de- 
velopment of  painful  sensations,  the  extremities  become  stiff  followed  by 

Vol.  I.  343 


BLIND   FLYING  579 

numbness  and  a  tendency  to  sleep.  The  fall  in  temperature  stimulates 
metabolism,  and,  therefore,  the  demand  for  oxygen  is  increased,  a  fact 
worthy  of  note,  at  high  altitudes,  where  extremes  of  cold  and  low  oxygen 
tension  are  encountered.  Heavy  clothing  is  inadequate  at  very  low  tem- 
peratures, and  it  further  restricts  free  movement.  Armstrong-  states 
that  at  -40°  F.,  there  is  a  loss  of  morale,  distraction,  acute  physical  suf- 
fering, muscular  sluggishness  and  incoordination  with  finally  a  tendency 
to  stupor. 

The  effects  of  wind  in  flying,  according  to  Aggazzotti^  and  Galeotti, 
are  such  as  to  cause  irregularity  and  acceleration  of  respiration  and  a 
diminution  in  alveolar  carbon  dioxide.  Strong  winds  may  interfere  with 
the  entrance  of  air  to  the  lungs,  hinder  movements  of  the  thorax  and  de- 
crease lung  ventilation.  Metabolism  will  be  increased  by  the  eff'ect  of 
wind  in  flying,  and  this  increases  the  demand  for  oxygen. 

With  the  use  of  cabin  ships  the  effects  of  wind  are  less  important  than 
in  open  ships  so  far  as  the  effect  on  the  pilot  is  concerned.  Pinson  and 
Benson^^  state  that  the  final  solution  to  the  problem  of  maintaining  body 
heat  under  the  varied  and  extreme  conditions  encountered  in  flight  is 
dependent  to  a  great  extent  on  future  developments  in  airplane  design. 
In  pressure  cabin  planes  heating  of  the  cabin  with  a  provision  for  de- 
frosting the  windows  may  be  the  answer.  At  present  they  recommend 
using  the  best  features  of  the  electrically  heated  suit  with  the  use  of  in- 
sulative  clothing  of  maximum  bulkiness  commensurate  with  normal 
personal  comfort  and  efficiency. 

Blind  Flying 

This  comes  rather  under  the  head  of  flying  training  than  under  avia- 
tion medicine.  Nevertheless,  the  difficulties  of  blind  flying  are  physiolog- 
ical, and  so  a  few  words  must  be  said  on  this  subject.  By  blind  flying 
is  meant  flying  without  a  horizon  for  guidance.  This  occurs  in  fogs,  thick 
weather  and  above  the  clouds.  We  have  seen  that  equilibrium  depends 
on  several  factors  and  one  of  these,  the  most  important  in  the  pilot,  is 
vision.  Vision  is  of  no  use  in  blind  flying.  Our  other  senses  are  unre- 
liable, and  hence  the  flyer  must  depend  on  instruments  to  determine  his 
position  in  space.  This  sounds  simple  but  is  not,  because  one's  physical 
sensations  are  overpowering  unless  he  has  been  specially  trained. 

That  vertigo  results  from  spinning  and  turning  is  well  known.  That 
this  vertigo  is  not  only  confusing  but  causes  false  sensations  of  direction 
is  not  so  well  understood.  However,  that  such  is  the  case  can  be  easily 
demonstrated  by  a  Barany  or  other  turning-chair. 

Vol.  I.  343 


580 


AVIATION   MEDICINE 


Fig.  II.  Apparatus  for  demonstrating  to  a  pilot  the  falsity  of  his  sensations  after  turn- 
ing. The  side  of  the  camera  has  been  removed  to  show  the  interior.  The  scheme  was  first 
suggested  by  Colonel  D.  A.  Myers,  U.  S.  Army  (Ret.).  Apparatus  perfected  by  Colonel 
W.  C.  Ocker,  U.  S.  Army. 


Vol.  I.  343 


BLIND   FLYING  581 

For  example,  if  the  applicant  is  turned  to  the  right  with  his  eyes 
closed  say  10  times  in  20  seconds,  he  at  first  has  a  sensation  of  turning 
to  the  left,  then  a  sensation  of  turning  to  the  right,  and  if  the  turning  rate 
then  is  slowed  or  stopped  altogether,  he  has  the  sensation  of  turning  to 
the  left.  If  he  opens  his  eyes,  the  falsity  of  his  sensations  is  apparent 
at  once. 

The  cause  of  these  sensations  is  due  to  stimulations  of  the  end  organs 
of  the  vestibular  branch  of  the  eighth  nerve  in  the  semicircular  canals. 
The  exact  physiological  phenomenon  has  been  a  source  of  great  dispute 
among  otologists,  but  it  is  pretty  generally  agreed  now  that  the  cause  is 
a  change  of  tension  in  the  fluid  in  these  canals.  For  our  purposes,  how- 
ever, the  exact  cause  is  not  important;  the  fact  that  such  sensations  occur 
is  the  factor  to  be  considered. 

The  practical  application  of  this  to  flying  is  the  following:  If  a  pilot 
flying  in  a  fog  gets  into  a  spin  and  then  comes  out  of  it,  he  has  the  sen- 
sation of  spinning  in  the  opposite  direction.  If  he  depends  on  this  sensa- 
tion, he  will  correct  for  the  supposed  spin  and  this  "correction"  at  once 
puts  him  into  another  spin.  This  may  keep  up  in  a  vicious  circle  until  he 
crashes.  His  only  hope  is  to  disregard  his  sensations  and  fly  by  instru- 
ments. 

Many  flyers  have,  in  the  past,  complained  after  blind  flights,  from 
which  fortunately  they  returned,  that  their  instruments  were  wrong  and 
were  disconcerting.  Without  some  such  demonstration  as  has  been  out- 
lined above  it  would  be  impossible  to  convince  these  flyers  that  their 
instruments  were  right  and  that  they  or  their  sensations  actually  were 
wrong. 

To  follow  one's  instruments  is  difficult  without  special  training,  be- 
cause these  erroneous  sensations  one  receives  are  overpowering  until  he 
has  been  trained  to  disregard  them.  In  this  connection  it  is  interesting 
to  note  that  Ocker'^^  found  trained  flyers  were  unable  to  fly  a  course  by 
instruments  without  re-education,  even  though  they  realize  its  necessity. 
They  had  been  flying  too  long  "by  feel"  to  be  able  suddenly  to  disregard 
their  sensations.  On  the  other  hand,  they  found  that  an  untrained  or 
rather  a  very  slightly  trained  flyer  could  do  fairly  well  because  he  had 
nothing  to  unlearn. 

Military  pilots  are  now  trained  in  blind  flying,  and  all  air  line  transport 
companies  also  train  their  flyers  in  it.  The  instruments  used  include  not 
only  an  altitude  indicator,  an  air  speed  indicator,  tachometer,  turn  and 
bank  indicator,  a  gyro  compass  as  well  as  a  magnetic  compass  but  an 
instrument  giving  an  artificial  horizon,  such  as  the  flight  integrator  of 
Ocker  and  Crane^^  or  a  gyro  horizon. 

Vol.  I.  343 


582  AVIATION   MEDICINE 


Care  of  the  Flyer 

Selection  of  the  flyer  is  only  part  of  the  problem,  important  though 
it  is.  Once  selected,  the  pilot  must  be  maintained  in  at  least  as  good 
condition  as  he  was  at  the  time  of  his  selection.  This  requires  frequent 
observation.  In  the  Army  and  Navy  flyers  are  all  under  the  constant 
supervision  of  a  trained  flight  surgeon.  Both  services  require  the  flyer 
to  check  out  daily  through  the  flight  surgeon  before  flying.  This  is  the 
ideal  arrangement.  The  flight  surgeon  becomes  thoroughly  acquainted 
with  his  flyers  and  knows  their  habits  and  weaknesses.  He  knows  which 
•flyer  needs  more  supervision,  which  takes  good  care  of  himself.  Aside 
from  the  required  semi  annual  examinations  frequent  checks  of  certain 
physical  points  are  made  as  developments  warrant.  In  the  service,  when- 
ever a  student  flyer  begins  to  fall  off  in  his  flying,  makes  poor  landings  or 
what  not,  he  is  sent  to  the  flight  surgeon  for  an  overhaul. 

Fatigue.  —  Flying  is  fatiguing,  and  too  much  of  it  results  in  "  state- 
ness" or  neurocirculatory  asthenia.  Not  only  too  much  flying  will  bring 
on  this  condition,  but  too  little  exercise,  too  little  recreation  or  too  much 
dissipation  likewise  will  do  it. 

Schneider^°' ^^  has  defined  fatigue  as  "a  progressive  flagging  of  effi- 
ciency together  with  a  subject  sensation  of  the  loss  of  control  of  the 
muscles".  Physiological  activity  becomes  lowered  and  the  ability  to  work 
is  diminished.  When  a  person  engages  in  normal  activity,  it  is  a  natural 
result  that  fatigue  ensues.  However,  this  fatigue  should  be  relieved  com- 
pletely by  a  night's  sleep.  When  it  is  not  relieved  and  the  activity 
responsible  for  it  continued,  there  will  be  an  accumulative  fatigue  which 
eventually  burns  up  the  reserve,  and  we  have  "staleness"  resulting. 

Stateness. — Schneider^^  has  defined  the  various  types  of  "staleness" 
as  follows:  (i)  Cardiorespiratory.  —  Pulse  increase  in  rate,  poor  in  vol- 
ume and  low  in  tension.  There  is  distress  on  slight  exertion  accompanied 
by  an  inordinate  rise  in  pulse  rate  and  prolonged  time  of  return  of  the 
pulse  after  exercise;  breathing  shallow  and  rapid;  extremities  poor  in 
color,  cyanotic  and  cold.  (2)  Nervous  type.  —  Poor  muscular  control  of 
balancing  movements;  fine  tremors  of  the  hands,  eyelids  and  tongue; 
apprehensive  starts  with  sudden  sensory  experiences;  disturbed  sleep; 
loss  of  sleep;  nightmare.  (3)  Muscular  type. — Tenderness  of  the 
muscles  with  loss  of  tone,  flabbiness,  loss  in  power  which  may  be  marked 
or  slight.  These  symptoms  may  be  confused  with  rheumatism.  (4)  Stale- 
ness may  be  brought  about  also  by  disorders  of  digestion  characterized  by 
removal  of  normal  inhibitions,  i.e.,  reponse  to  sensory  stimuli  by  excess 

Vol.  I.  343 


CARE  OF   THE   FLYER  583 

of  motion,  hypersensitiveness,  annoyance  by  bright  light,  little  noises,  etc., 
restlessness. 

Bainbridge^  considers  "staleness"  as  nothing  more  or  less  than  "effort 
syndrome".  It  results  from  severe  exertion  or  in  the  course  of  training, 
and  the  circulatory  and  respiratory  changes  which  occur  normally  are 
increased.  He  further  believes  that  the  contractile  power  of  the  heart  is 
diminished  and  that  oxygen  want  plays  a  part  in  functioning  of  the 
muscles  and  nervous  system.  The  changes  in  pulse,  respiration  and  blood 
pressure  result  from  an  insufficient  supply  of  oxygen. 

Effort  syndrome  or  neurocirculatory  asthenia  was  described  first  by 
Lewis^^  He  describes  four  groups  of  cases.  These  are  (i)  constitutional 
or  hereditary  group,  (2)  a  group  due  to  exposure  and  mental  or  physical 
strain,  (3)  convalescent  group,  (4)  toxic  group. 

The  symptoms  are,  in  the  order  of  importance,  breathlessness  brought 
on  by  exertion,  the  rate  of  breathing  being  markedly  increased  by  exercise; 
pain,  usually  this  is  exaggerated  by  exercise;  exhaustion,  even  mild  cases 
show  fatigue  on  moderate  exertion,  and  palpitation  is  common;  giddiness 
is  more  or  less  constant  and  is  associated  with  change  of  posture  and 
effort;  fainting  may  occur;  other  symptoms  are  headache,  lassitude,  irri- 
tability, sleeplessness,  inability  to  fix  attention,  coldness  of  the  hands  and 
feet,  sweating,  particularly  of  the  hands,  feet  and  axillae. 

The  physical  signs  are  increased  heart  rate  and  particularly  an  exag- 
gerated response  of  the  heart  to  exercise  with  a  slow  return  of  the  pulse 
after  exercise.  There  are  exaggerated  responses  of  the  blood  pressure, 
although  frequently  we  find  that  upon  change  of  posture  the  blood  pres- 
sure falls  rather  than  rises.  The  apex  beat  may  be  diffuse  and  the  heart 
sounds  accentuated.  Functional  systolic  murmurs  may  be  present. 
There  is  an  exaggeration  of  the  deep  reflexes  and  coarse  tremor  of  the 
hands  and  tongue.  The  symptoms  of  an  individual  case  may  be  anything 
from  breathlessness  up  to  a  definite  picture  presenting  the  above  symp- 
toms. The  stale  flyer  presents  much  the  same  picture.  The  flight  surgeon 
should  be  continually  on  the  watch  for  the  development  of  this  condition. 
It  must  be  caught  in  its  incipiency,  for  if  it  is  allowed  to  develop,  not 
only  may  a  serious  accident  occur,  but  recovery  becomes  prolonged  and 
uncertain.  Staleness  may  be  prevented  by  maintaining  a  condition  of 
physical  fitness.  Exercise  and  proper  rest  are  the  essential  factors  in  this 
program. 

Bainbridge^  states  that  training  develops  the  skeletal  muscles  and  also 
the  heart.  A  person  in  training  shows  a  slower  pulse,  lower  blood  pressure 
and  a  lessened  minute  volume  of  the  heart.  The  heart  output  is  greater 
per   beat,   and    the   oxygen   carrying   power   of   the   blood   has   a   greater 

Vol.  I.  343 


584  AVIATION   MEDICINE 

coefficient  of  utilization.  Movements  are  better  coordinated,  and  there  is 
a  better  economy  of  effort. 

The  development  of  staleness  results  in  a  dislike  of  flying  and  a  loss 
of  flying  efficiency.  Poor  landings,  the  loss  of  the  "feel  of  the  ship", 
neglect  of  details  such  as  attention  to  instruments,  position  of  stabilizer, 
neglect  of  altitude  adjustment  and  incorrect  computations  of  gas  expen- 
ditures may  result.  Poor  judgment  becomes  common,  and  the  flyer 
does  not  make  prompt  decisions. 

Staleness  is  insidious  in  its  development,  and  frequent  medical  super- 
vision is  important.  In  civilian  flying  constant  medical  supervision  is  not 
practicable.  Its  importance,  however,  is  considered  so  great  that  several 
air  lines  in  the  United  States  employ  flight  surgeons  to  check  the  physical 
condition  of  their  pilots  monthly. 

Wright^^  feels  that  a  pre-employment  examination  is  essential  in  order 
that  the  pilots  can  be  certified  for  their  positions,  not  only  in  regard  to 
their  present  state  of  health  and  efficiency  but  to  prognosticate  their 
adaptability  to  conditions,  their  reliability  and  stamina.  He  feels  that 
the  Schneider  index  is  an  excellent  method  of  keeping  track  of  the  flyer's 
physical  efficiency.  This  test  was  devised  by  Schneider^"  primarily  for 
use  in  following  the  physical  condition  of  aviators.  It  will  be  described 
later  in  the  chapter. 

Miller  and  Ginsberg^*  studied  metabolic  and  serological  changes  in 
flight  fatigue  in  a  group  of  pilots.  They  found  hypotension  was  common 
after  flight  and  wondered  whether  or  not  this  was  an  evidence  of  fatigue. 
They  made  determinations  of  basal  metabolic  rate,  blood  sugar,  creatinine 
and  non-protein  nitrogen  before  and  after  flight  in  a  group  of  15  pilots. 
They  also  took  Schneider  tests  and  flarimeter  tests  on  the  same  group. 

A  brief  summary  of  the  work  follows:  "Fifteen  veteran  pilots  have 
been  studied.  Forty-six  and  six-tenths  per  cent,  of  these  pilots  show  a 
lower  basal  metabolic  rate  after  flying  in  comparison  to  the  basal  meta- 
bolic rate  found  after  resting.  Blood  sugar  values  were  low.  Identical 
values  were  almost  always  found  for  blood  sugar  after  flying  and  after 
rest.  Creatinine  determinations  show  no  change.  Non-protein  nitrogen 
determinations  show  that  forty-six  and  six-tenths  per  cent,  give  higher 
values  after  rest,  but  this  group  is  not  related  to  the  group  showing  higher 
basal  metabolic  rates  after  flying.  The  Schneider  index  permits  us  to 
conclude  that  a  pilot  has  a  more  efficient  neurocirculatory  mechanism 
after  rest."  They  suggested  that  the  hypotension  may  be  a  sign  of  phys- 
ical fatigue  caused  by  drain  or  exhaustion  of  the  adrenals.  Flying  causes 
fear  in  the  novice,  and  this  gradually  becomes  more  or  less  repressed  into 
the  unconscious.    Fatigue  is  induced  more  quickly  by  flying  in  bad  weather 

Vol.  I.  343 


CARE   OF   THE   FLYER  585 

or  over  unfavorable  territory.  This,  they  feel,  forms  the  basis  of  emo- 
tional stress.  They  state:  "Our  findings  lead  us  to  believe  that  there  is 
possibly  a  drain  on  the  suprarenals  during  flying,  whether  it  is  physical 
or  mental.  It  might  then  follow  that  an  exhausted  suprarenal  gland  may 
affect  the  sympathetic  nervous  system  in  such  a  way  as  to  reduce  its 
tonicity.  Further,  this  drain  or  exhaustion  of  the  adrenals  is  probably 
the  cause  of  fatigue  with  its  eissociated  hypotension.  Our  opinion  is  that, 
due  to  prolonged  emotional  stress,  the  sympathetic  nervous  system 
stimulates  adrenalin  secretion,  which  causes  a  decrease  in  the  liver  and 
muscle  glycogen.  Exhaustion  of  the  liver  glycogen  calls  forth  the  manu- 
facture of  carbohydrate  from  protein  and  possibly  fat,  resulting  in  the 
tearing  down  of  tissues.  This  anabolism  produces  an  increase  in  the  acids, 
and  these  acids  in  turii  stimulate  the  respiratory  centers  to  cause  increased 
pulmonary  ventilation.  This  is  necessary  to  keep  pace  with  the  demand 
for  oxygen.  Our  blood  sugar  findings  are  low.  This  denotes  increased 
sugar  consumption,  and  as  the  energy  is  needed,  the  demand  becomes 
greater  on  the  adrenals  until  we  have  a  depletion  and  adrenalemia  with 
resulting  fatigue  and  hypotension." 

Padden"  reports  that  irregular  hours  and  excessive  flying  affect 
ocular  muscle  balance  early.  He  lays  great  stress  on  goggles  and  states 
that  many  difficulties  are  encountered  due  to  optically  imperfect  lenses  in 
the  goggles.  He  recommends  frequent  checking  of  goggles  to  protect  the 
.eyes  of  the  flyer. 

Flyers  are  particularly  prone  to  develop  gastrointestinal  upsets,  prob- 
ably due  partly  to  emotional  stress  and  partly  to  the  irregular  hours  and 
irregular  meals.  One  transport  operator  had  16  per  cent,  of  his  pilot 
personnel  develop  acute  appendicitis  in  13  months.  All  these  cases  were 
operated  on,  and  in  all  instances  the  attack  came  on  from  within  5  minutes 
to  2  hours  of  takeofif  and  in  one  pilot  while  flying  his  run.  Gastric  ulcer 
is  not  infrequent  and  probably  due  to  the  same  causes. 

Diseases  of  the  upper  respiratory  passages  due  to  exposure  to  cold  and 
fatigue,  middle  ear  troubles,  particularly  in  altitude  flights,  are  common. 

All  these  factors  show  the  need  for  medical  supervision.  One  flight 
surgeon  reported  that  the  efTect  of  irregular  schedules,  meals,  sleep  and 
recreation  showed  by  frequent  minor  accidents,  poor  morale  among  pilots, 
staleness  and  a  marked  decrease  in  general  physical  fitness.  Flying  then 
causes  fatigue,  and  this  may  cause  various  physical  ailments  and  even- 
tually may  develop  into  staleness;  a  falling  off  in  flying  ability  occurs, 
and  nervous  instability  results. 

The  flight  surgeon  must  detect  such  conditions  early  and  take  the 
necessary  measures  to  prevent  a  state  developing  that  will   necessitate 

Vol.  I.  343 


586  AVIATION    MEDICINE 

complete  removal  from  flying  status,  or  that  will  result  in  accidents. 
Careful  selection,  regular  exercise,  avoidance  of  too  much  flying,  adequate 
rest  and  recreation  will  prevent  staleness.  Laboratory  examinations 
should  play  a  part  in  the  supervision  of  pilots  as  pointed  out  by  Tillisch 
and  Lovelace^^.  They  found  73  of  103  pilots  had  defects,  which  did  or 
could  affect  their  health.  Many  of  these  defects  would  have  gone  un- 
recognized in  an  ordinary  physical  examination. 

The  Army  Flight  Surgeon's  Handbook^^  recommends  that  the  limita- 
tion of  flying  hours,  as  given  later  under  "Flying  time,"  should  be  ad- 
hered to.  The  Army  also  feels  that  on  completion  of  a  mission  crews 
should  be  taken  3  to  5  miles  away  from  the  airdrome  for  rest  and  sleep. 
Attention  is  called  to  the  fact  that  mild  degrees  of  anoxia  increase  fa- 
tigue. Strict  oxygen  discipline  should  be  insisted  upon.  New  personnel 
joining  operational  units  should  be  watched  carefully,  as  inadequacies 
are  apt  to  crop  up  early.  It  is  advised  that  flying  stress,  once  developed, 
should  be  treated  only  in  a  hospital.  They  consider  flying  stress  is  "in- 
fectious". 

McFarland^"  in  an  excellent  treatise  on  fatigue  in  aircraft  pilots  shows 
that  a  pilot  whose  muscular  activity  in  flight  is  limited  could  hardly  ex- 
haust the  energy  reserves  sufficiently  to  explain  the  fatigue  and  exhaustion 
often  observed  in  airmen.  He  ascribes  the  acute  and  chronic  pilot  fa- 
tigue and  exhaustion  to  psychological  factors  such  as  emotional  stress 
regardless  of  whether  it  is  related  to  adverse  flying  conditions,  fear  of 
accident,  economic  and  social  insecurity  and  unhappy  marital  adjustments. 
He  also  considers  lack  of  exercise,  reduced  oxygen  tension  in  high  altitude 
flights,  poor  selection  of  food  and  excessive  use  of  tobacco  and  alcohol 
as  contributing  factors  to  fatigue.  Other  variable  contributing  factors  are 
noise,  vibration,  poor  illumination,  glare,  static  from  the  radio  and  poor 
regulation  of  ventilation  and  temperature. 

Physical  fitness  is  more  important  in  flying  than  in  any  other  occupa- 
tion. The  necessity  of  constant  medical  supervision,  or  as  near  constant 
as  practicable,  cannot  be  too  strongly  emphasized. 

The  technique  of  the  Schneider  test  already  mentioned  is  described  below: 

DIRECTIONS    FOR     PROCEDURE     IN    THE    CIRCULATORY     EFFICIENCY 
TEST    (SCHNEIDER    INDEX)3o 

Preliminary:    Subject  reclines  for  five  minutes. 

1.  Heart  rate  is  counted  for  20  seconds.     When  two  consecutive  20  second  counts  are 

the  same,  this  is  multiplied  by  3  and  recorded. 

2.  The  systolic  pressure  is  taken  by  auscultation  and  recorded.     Take  two  or  three 

readings  to  be  certain. 

Vol.  I.  343 


FLYING  TIME   FOR   PILOTS  587 

3.  The  subject  then  rises  and  stands  for  two  minutes  to  allow  the  pulse  to  assume  a 

uniform  rate.  When  two  consecutive  15  second  counts  are  the  same,  multiply  by 
4  and  record.     This  is  the  normal  standing  rate. 

4.  Standing  pulse  minus  the  reclining  pulse  gives  the  increase  on  standing. 

5.  The  systolic  pressure  is  taken  as  before  and  recorded. 

6.  Timed  by  a  stopwatch,  the  subject  steps   upon  a  chair   18^  inches  high   five   times 

in  15  seconds.  To  make  this  uniform  the  subject  stands  with  one  foot  on  the  chair 
at  the  count  one.  This  foot  remains  on  the  chair  and  is  not  brought  to  the  floor 
again  until  count  five.  At  each  count  he  brings  the  other  foot  on  the  chair,  and 
at  the  count  "down"  replaces  it  on  the  floor.  This  should  be  timed  accurately  so 
that  at  the  15  second  mark  on  the  stopwatch  both  feet  are  on  the  floor. 

7.  Start  counting  the  pulse  immediately  at  the  15  second  mark  on  the  stopwatch  and 

count  for  15  seconds.     Multiply  by  4  and  record. 

8.  Continue  to  take  pulse  in  15  seconds  counts  until  the  rate  has  returned  to  normal 

standing  rate.  Note  the  number  of  seconds  it  takes  for  this  return  and  record. 
In  computing  this  return  count  from  the  end  of  the  15  seconds  of  exercise  to  the 
beginning  of  the  first  normal  15  seconds  pulse  count.  If  the  pulse  has  not  returned 
to  normal  at  the  end  of  2  minutes,  record  the  number  of  beats  above  normal 
and  discontinue  counting. 

9.  Check  up  points  and  enter  final  rating. 

10.  Enter  history  of  case,  including  amount  of  sleep,  amount  of  smoking,  kind  of  work 
(outdoor  or  indoor,  active  or  sedentary,  etc.),  time  since  last  meal,  any  personal 
worries  or  any  pathological  condition  which  might  affect  the  condition  of  the  sub- 
ject. The  test  should  not  be  made  within  2  hours  after  a  meal,  and  the  habits  of 
the  individual  must  be  taken  into  consideration. 

Roughly,  an  index  of  14  to  18  is  excellent;  10  to  13  very  good;  7  to 
9  borderline;    below  7  unsatisfactory. 

Scott^-  by  means  of  systematic  exercise  over  a  period  of  one  month 
improved  the  average  index  of  a  group  of  flyers.  The  results  before  the 
exercise  was  started  were  20  per  cent.  14  or  above;  60  per  cent.  8  to  13; 
and  20  per  cent.  7  or  less.  At  the  end  of  the  month  the  results  were  80 
per  cent.  14  or  above;    10  per  cent.  8  to  13  and  10  per  cent.  7  or  less. 

As  a  gauge  of  condition  in  athletes,  flyers  and  those  subjected  to 
constant  mental  strain,  whose  condition  may  be  checked  from  time  to 
time,  it  is  probably  the  most  satisfactory  test  yet  devised. 

Flying  Time  for  Pilots 

This  is  a  much  mooted  question,  but  as  flying  is  fatiguing  and  apt  to 
induce  staleness  if  overindulged  in,  a  limit  in  the  amount  of  flying  a  man 
should  do  must  be  set  in  the  interest  of  safety  and  efficiency.  The  Army 
considers  100  hours  per  month  as  the  limit,  and  its  pilots  are  under  con- 
stant medical  supervision.  Taken  as  a  whole,  peace  time  flying  in  the 
Army  with  its  associated  military  duties  may  be  compared  with  transport 
flying  from  the  physical  standpoint. 

Vol.  I.  343 


588 


AVIATION    MEDICINE 


TABLE   OF   POINTS  FOR   GRADING   CARDIOVASCULAR 
CHANGES    IN   THE   SCHNEIDER    INDEX 


A.    Reclining  pulse  rate 

B.    Pulse  rate  increases  on  standing 

Rate 

Points 

o-io  beats, 
points 

11-18  beats, 
points 

19-26  beats, 
points 

27-34  beats, 
points 

35-42  beats, 
points 

50-60 

3 

3 

3 

2 

I 

0 

61-70 

3 

3 

2 

I 

0 

-I 

71-80 

2 

3 

2 

0 

-I 

-2 

81-90 

I 

2 

I 

-I 

-2 

-3 

91-100 

0 

I 

0 

-2 

-3 

-3 

lOI-IIO 

-I 

0 

-I 

-3 

-3 

-3 

C.    Standing  pulse  rate 

D.    Pulse  rate  increase  immediately  after  exercise 

Rate 

Points 

o-io  beats, 
points 

11-20  beats, 
points 

21-30  beats, 
points 

31-40  beats, 
points 

41-50  beats, 
points 

60-70 

3 

3 

3 

2 

I 

0 

71-80 

3 

3 

2 

I 

0 

0 

81-90 

2 

3 

2 

I 

0 

-I 

91-100 

I 

2 

I 

0 

-I 

-2 

lOI-IIO 

I 

I 

0 

-I 

-2 

-3 

111-120 

0 

I 

-I 

-2 

-3 

-3 

121-130 

0 

0 

-2 

-3 

-3 

-3 

131-140 

I 

0 

-3 

-3 

-3 

-3 

E.    Return    of    pulse    rate    to    standing 

F.    Systolic  pressure,  standing, 

normal  after  exercise 

compared  with  reclining 

Seconds 

Points 

Change  in  millimeters 

Points 

0-30 

3 
2 

3 
2 

31-^0 . 

Rise  of  2-7 

61-90  

I 

No  rise 

I 

91-120     

0 

Fall 

of  2—5;               

0 

After    120:     2-10   beats   above 

normal 

-I 

Fall  of  6  or  more 

-I 

After  120:    11-30  beats  above 

normal 

—■> 

The  test  must  be  performed  accurately  and  painstakingly.     Also  one  index  is  not  of 
much  value.     Several  should  be  had  in  order  to  afford  a  basis  for  comparison. 
Vol.  I.  343 


AIR   SICKNESS  589 

Air-line  flying  may  be  divided  into  day  and  night  flying.  To  deal 
first  with  the  former,  it  is  believed  that  the  air-line  regulations,  which  in 
peace  time  limit  the  total  flying  of  any  pilot  to  85  hours  per  month,  is 
reasonable.  Poor  terrain,  heavy  passenger  loads,  poor  average  weather 
conditions  and  lack  of  a  co-pilot  should  reduce  the  maximum.  Good 
terrain,  the  presence  of  a  co-pilot  and  good  average  weather  conditions 
may  increase  it  somewhat,  perhaps  to  100  hours.  Or  in  the  case  of  re- 
peated short  flights  under  good  conditions,  perhaps  slightly  more. 

As  to  night  flying,  this  is  admittedly  more  hazardous  and  more  of  a 
strain.  With  the  same  factors  acting  in  modification,  a  limit  of  60  to  75 
hours  per  month  is  desirable. 

In  advancing  any  limits,  however,  it  should  be  assumed  that  the  pilot 
obtains  sufficient  sleep  each  day  under  restful  conditions  to  give  the  neces- 
sary recuperation  from  exhaustion  and  place  him  in  condition  to  resume 
flying. 

The  commercial  pilot  should  have  one  or  more  days  a  week  ofif  from 
flying.  Under  good  flying  conditions  one  day  may  be  sufficient,  but  under 
more  trying  conditions  every  third  or  fourth  day  should  be  taken  off.  In 
addition,  the  pilot  should  have  from  three  to  four  weeks  a  year  off. 
Whether  one  vacation  of  four  weeks  is  better  than  two  vacations  of  two 
weeks  each  is,  perhaps,  still  open  to  argument,  but  that  it  should  not  be 
subdivided  more  than  that  is  generally  agreed  by  medical  men. 

Because  of  the  war  limitation  of  flying  hours  has  been  removed,  and 
already  many  pilots  have  complained  of  marked  fatigue,  inadequate  rest 
periods,  and  the  excellent  record  for  safety  made  during  the  past  several 
years  by  the  air  lines  of  the  United  States  will  be  in  grave  danger. 

In  military  operations  it  is  important  to  space  operations  for  the  pilot 
as  evenly  as  possible.  Ninety  to  no  operational  hours  in  six  weeks  has 
been  recommended  for  fighter  pilots  and  120  to  139  hours  of  operational 
flying  for  bombers  in  three  months.  Leaves  should  be  given  then  followed 
by  a  period  of  flying  not  involving  operations  before  return  to  operational 
duty. 

The  Army  feels  that  7  days  is  as  long  a  leave  as  should  be  given  but 
that  this  should  be  given  at  stated  intervals.  One-half  a  day  off  should  be 
given  every  3  or  4  days;  48  hours  every  2  weeks  and  7  days  at  the  end  of 
the  operational  limit. 

Air  Sickness 

Sea-sickness  has  been  known  ever  since  man  took  to  the  sea,,  and  air- 
sickness became  fairly  common  after  flying  became  prevalent.     The  cause 
Vol.  I.  343 


590  AVIATION   MEDICINE 

of  air-sickness  is  the  same  as  the  cause  of  sea-sickness,  namely  unaccus- 
tomed motion  with  overstimulation  of  the  vestibular  mechanism.  We 
have  other  similar  forms  of  sickness,  namely  train  sickness,  swing  sickness, 
etc.,  all  of  which  are  due  to  the  same  cause. 

The  airplane  moving  through  a  rather  unstable  medium  is  similar  to  a 
ship  plowing  through  pitching  seas.  The  air  is  smooth  on  some  days  and 
rough  on  others.  On  windy  or  gusty  days  the  air  is  rough.  Likewise  on 
days,  on  which  there  has  been  a  sudden  drop  in  temperature,  the  air  is 
rough  and  bumpy,  due  to  the  fact  that  the  air  is  not  uniformly  cooled, 
and  we  meet  warm  and  cold  currents  of  air  alternately.  The  air  usually 
is  bumpy  over  mountains  and  in  crossing  bodies  of  water  from  the  land. 
This  unaccustomed  motion  stimulating  our  motion  sensing  apparatus  causes 
a  certain  amount  of  vertigo  and  nausea. 

Some  people  are  more  prone  to  air-sickness  than  others,  just  as  is  the 
case  with  sea-sickness.  The  nervous,  high  strung  type  of  individual  is 
more  apt  to  be  air-sick  than  the  phlegmatic  type.  Fear  often  acts  as  an 
exciting  cause  for  air-sickness.  There  is,  therefore,  a  psychological  factor 
in  air-sickness  aside  from  the  physical  factor.  The  person,  who  is  car- 
sick or  sea-sick,  probably  will  be  air-sick  also. 

There  are  certain  measures  to  be  carried  out  as  a  prophylactic.  The 
passenger,  for  pilots  are  rarely  air-sick,  should  avoid  eating  rich  or  heavy- 
food  before  flying.  He  should  be  instructed  to  swallow  frequently  as  this 
keeps  his  Eustachian  tubes  open  and  prevents  pain  developing  from  re- 
tracted ear  drums  on  sudden  change  of  altitude.  Chewing  gum  facilitates 
keeping  the  Eustachian  tubes  open.  The  passenger  also  should  have  his 
attention  diverted  as  much  as  possible.  If  he  can  be  encouraged  to  follow 
a  map,  it  takes  his  mind  off  himself  and  prevents  fear.  If  he  actually 
becomes  sick,  he  should  be  made  to  go  to  the  wash-room  to  avoid  up- 
setting other  passengers.  An  alkaline  effervescent  drink  is  recommended 
by  Wright^^  as  a  cure  for  nausea  in  the  air.  If  food  is  taken,  toast,  plain 
crackers  or  an  apple  are  less  upsetting  to  an  air-sick  passenger  than  heavy 
food  or  liquid  except  for  an  alkaline  drink. 

Both  Padden^^  and  Wright^^  recommend  a  grain  or  two  of  amytal 
for  a  nauseated  passenger.  Wright  states  such  a  passenger  often  will 
drop  off  to  sleep  and  awake  feeling  refreshed  enough  to  enjoy  the  remain- 
der of  the  trip. 

Just  as  the  person  used  to  the  sea  is  less  apt  to  be  sea-sick  than  one 
who  rarely  sails,  so  the  one  who  flies  frequently  is  less  apt  to  be  air-sick. 
Pilots  rarely  are  air-sick,  partly  because  they  are  so  used  to  flying  and 
partly  because  they  are  busy  and  have  no  time  to  think  about 
themselves. 

Vol.  I.  343 


BIBLIOGRAPHY  59i 

The  frequency  of  air-sickness  is  disputed.  Some  authorities  claim  it 
occurs  in  5  per  cent,  of  passengers,  but  this  probably  is  too  high.  A  great 
deal,  of  course,  depends  on  flying  conditions.  On  a  smooth  day  only 
rarely  is  a  person  air-sick,  while  on  a  rough  day  more  are  sick.  Tuttle^* 
found  in  a  survey  of  the  United  Air  Line  flights  that  the  rate  of  air-sick- 
ness was  only  3  per  100.  He  classified  all  discomfort  in  air-line  planes  as 
follows : 

Air-sickness  0.33% 

Nervousness  0.09% 

Oxygen  want  0.08% 

Ear  trouble  0.05% 

All  others  0.05% 

Total  0.60% 

Conclusion 

Aviation  Medicine,  therefore,  has  an  important  field.  By  means  of  it 
the  public  is  assured  of  safety  in  flying  so  far  as  the  physical  side  is  con- 
cerned. It  includes  a  broad  knowledge  of  medicine  and  psychology  and  a 
personality  in  the  flight  surgeon  that  inspires  confidence  and  respect. 


BIBLIOGRAPHY 

1.  AGGAZZOTTI,  A.:    Influenza  del  vento  sulla  funzione  respiratoria  e  nil  polso, 

Gior.  di  Med.  Mil.,  1919,  LXVII,  107. 

2.  ARMSTRONG,    H.   G.:    The    Principles  and   Practice   of  Aviation  Medicine, 

Williams  and  Wilkins  Co.,  Baltimore,  1939. 

3.  BAINBRIDGE,  F.  A.:   The  Physiology  of  Muscular  Exercise,  Longmans  Green, 

New  York  and  London,  19 19. 

4.  BARACH,  A.  L.:    Principles  of  aviation  medicine.  War  Medicine:    a  sympo- 

sium. Philosophical  Library,  N.  Y.,  CCCXXXVI,  1942- 

5.  BEHNKE,  A.  R.,  Jr.:    Investigations  concerned  with  problems  of  high  altitude 

flying  and  deep  diving;    application  of  certain  findings  pertaining  to  phys- 
ical fitness  to  the  general  military  service,  Mil.  Surg.,  1942,  XC,  9. 

6.  BERENS,  CONRAD:    Present  ophthalmologic  standards  for  commercial  avia- 

tion in  the  United  States,  Jour.  Aviation  Med.,  1932,  CXI,  55. 

7.  BOOTHBY,  W.  M.  and  LOVELACE,  W.  R.,  II:    Oxygen  in  aviation.  Jour. 

Aviat.  Med.,  1938,  IX,  172. 

8.  CARLSON,   W.   A.:     Psychology  and   aviation,   Jour.  Aviat.  Med.,    1939,   X, 

216. 

9.  COOPER,  H.  J.:    The  relation  between  physical  deficiency  and  decreased  per- 

formance. Jour.  Aviation  Med.,  1930,  I,  5. 
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592  AVIATION   MEDICINE 

10.  COOPER,  H.  J.:    Further  studies  on  the  effect  of  physical  defects  and  flying 

ability,  Jour.  Aviat.  Med.,  1931,  II,  162. 

11.  Flight  Surgeon's  Handbook,  The  School  of  Aviation  Medicine,  Randolph  Field, 

Texas,    1942. 

12.  FLYNN,  V.   P.:    Clinical   test  for  dark  adaptation,  Jour.  Aviat.   Med.,   1942, 

XIII,  216. 

13.  FULTON,   JOHN   F.:    Physiology  and   high   altitude   flying;    with   particular 

reference  to  air  embolism  and  the  effects  of  acceleration.  War  Medicine: 
a  symposium.   Philosophical  Library,  N.  Y.,  CCCXXXVI  1942. 

14.  GARSAUX,   P.:    Results  of  the  experiments  on  the   12th  and   17th  of  July, 

191 8  from  the  action  of  centrifugal  force  on  dogs  (translation),  Experi- 
mental service,  technical  section,  military  aeronautics,  Ofifice  of  Minister  of 
War,  Paris,  191 8. 

15.  HERBOLSHEIMER,  A.  J.:    A  study  of  300  non-selected  aviation  accidents. 

Jour.  Aviat.  Med.,  1942,  XIII,  256. 

16.  HOWARD,   H.  J.:    A  test  for  the  judgment  of  distance.  Am.  Jour.   Ophth., 

1919,  3  s.,  II,  656. 

17.  JARMAN,   B.   L. :    Monocular  vision  and  other  peculiar   phases  of   flying  as 

regards  depth  perception,  Jour.  Aviat.  Med.,  1932,  III,  194. 

18.  LEWIS,   T.:    The   Soldier's   Heart  and   the   Effort  Syndrome,    P.    B.    Hoeber, 

N.  Y.,  1920. 

19.  LONGACRE,  R.  F.:    Personality  study.  Jour.  Aviat.  Med.,  1930,  I,  33. 

20.  LONGACRE,  R.  F. :    Department  of  Commerce  conference.  Jour.  Aviat.  Med., 

1931,  II,  361. 

21.  MASHBURN,  N.  C:    Mashburn  automatic  serial  reaction  apparatus  for  de- 

tecting flying  aptitude.  Jour.  Aviat.  Med.,  1934,  V,  155. 

22.  McFARLAND,    ROSS   A.:    Fatigue   in   aircraft  pilots,  War  Medicine,   Philo- 

sophical Library,  N.Y.,  CCCXXXVI,  1942. 

23.  McFARLAND,  ROSS  A.,  GRAYBIEL,  A.,  LILJENCRANTZ,  E.  and  TUT- 

TLE,  A.  D.:  An  analysis  of  the  physiological  and  psychological  charac- 
teristics of  two  hundred  civil  air-line  pilots.  Jour.  Aviat.  Med.,  1939,  X, 
206. 

24.  MILLER,  W.  H.  and  GINSBERG,  A.  M.:    Metabolic  and  serologic  changes  in 

flight  fatigue;    preliminary  report,  Jour,  Aviat.  Med.,  1931,  II,  155. 

25.  OCKER,  W.  C.  and  CRANE,  C.  J.:    Blind  Flight,  in  Theory  and  Practice, 

Naylor  Printing  Co.,  San  Antonio,  Tex.,  1932. 

26.  ONFRAY,    R.:     Aviateurs,    XIII,    Concilium    Ophthalmologicum,    Hollandia, 

N.  V.  Boeken  Steendrukkerij,  Edward  Ljdo,  Leiden,  1929. 

27.  PADDEN,  E.  H.:    Observations  of  monthly  examinations  on  flying  personnel, 

Jour.  Aviat.  Med.,  1930,  I,  154. 

28.  PINSON,  E.  A.  and  BENSON,  O.  O.,  Jr.:    Problems  inherent  in  the  protection 

of  flying  personnel  against  temperature  extremes  encountered  in  flight, 
Jour.  Aviat.  Med.,  1942,  XIII,  43. 

29.  SCHNEIDER,  EDW.  C:  The  human  machine  in  aviation,  Yale  Review,  March 

1922,  New  Haven. 
Vol.  L  343 


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30.  SCHNEIDER,   EDW.  C:    Further  observations  on  a  cardiovascular  physical 

fitness  test,  Mil.  Surg.,  1923,  LIII,  401. 

31.  SCHNEIDER,  EDW.  C:    Unpublished  lecture  notes  on  aviation  physiology, 

The  School  of  Aviation  Medicine,  U.  S.  Army,   1924. 

32.  SCOTT,  VERNER  T. :    Daily  exercise  a  factor  in  preventive  medicine.   Mil. 

Surg.,  1922,  I,  648. 

33.  TILLISCH,  J.   H.  and   LOVELACE,   W.    R.,   II:    The   physical    maintenance 

of  transport  pilots.  Jour.  Aviat.  Med.,  1942,  XIII,  121. 

34.  TUTTLE,  A.  D.:   Safety  and  comfort  aloft.  Jour.  Aviat.  Med.,  1939,  X,  72. 

35.  U.  S.  Army:    Outline  of  Adaptability  Rating  for  Military  Aeronautics,  to  be 

published. 

36.  WRIGHT,  HERBERT  B.:   Medical  supervision  of  air  lines.  Jour.  Aviat.  Med., 

1932,  HI,  182. 

General  References 

ARMSTRONG,  H.  G.:  The  Principles  and  Practice  of  Aviation  Medicine,  Williams 
and  Wilkins  Co.,  Baltimore,  1939. 

BAUER,  L.  H.:   Aviation  Medicine,  Williams  and  Wilkins  Co.,  Baltimore,  1926. 

Handbook  for  Medical  Examiners,  Dept.  of  Commerce,  Civil  Aeronautics  Adminis- 
tration, 2d  edition,  Washington,  1942. 

March  i,  1943.  ' 


Vol.  I.  343 


594  AVIATION    MEDICINE 

Pages  594  to  6i8  will  be  supplied  at  a  later  date  by  another  article. 


Vol.  I.  343 


CHAPTER  XV      . 

THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

(Medical  Logic) 

By  LEWELLYS  F.  BARKER 

Table  of  Contents 

Development  of  Clinical  Diagnosis .  619 

Relationships  of  the  Science  of  Clinical  Diagnosis 622 

to  Physics 625 

to  Chemistry 627 

to  Biology 629 

to  Psychology 631 

to  Sociology 633 

to  Preclinical  Medical  Sciences 634 

The  Pure  Science  of  Clinical  Diagnosis 636 

The  Applied  Science  of  Clinical  Diagnosis 637 

The  Art  of   Clinical  Diagnosis 639 

The  Actual  Process  of  Clinical  Diagnosis 643 

Recognition  of  the  Problem 644 

Accumulation  of  Data 646 

Summarising  and   Arranging  the   Data 668 

Elaboration  by  Reasoning  of  Diagnostic  Inferences       .        .        .  676 

Testing  of  Inferences  and  Arriving  at  Diagnostic  Conclusions   .  680 

In  making  a  diagnostic  survey,  we  recognize  the  existence,  or 
absence,  of  "  disease  "  in  a  person  through  determining  the  presence,  or 
absence,  of  certain  symptoms  or  signs,  drawing  inferences  from  our 
findings,  reasoning  out  the  impHcations  of  these  inferences,  testing  them 
for  their  vaHdity,  and  finally  arriving  at  the  concluding  belief  that  "  dis- 
ease "  has  been  identified,  or  that  the  person  is  "  healthy."  It  is,  mainly, 
the  logical  basis  and  the  technique  of  the  process  that  will  be  discussed 
in  the  present  article. 

Development  of  Clinical  Diagnosis 

During  the  long  period  in  which  human  beings  have  lived,  enjoyed, 
and  suffered,  there  has  gradually  grown  up  a  body  of  opinions  and 
beliefs  regarding  health  and  disease.  At  all  times,  animals  and  human 
beings  have  been  subject  to  accidents  and  diseases  that  entail  suffering 

619 


620         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

or  disability.  A  human  being  who  suffers  pain  or  who  is  conscious  of 
disability  desires,  and  seeks,  relief.  Other  human  beings  who  see  him 
suffer  have  their  interest  and  sympathy  aroused  and  desire  to  help  him 
or  to  find  someone  who  can  help  him.  Even  among  the  primitive  healers, 
who  called  upon  the  gods  to  cure,  or  made  use  of  magic  arts  and 
enchantments,  there  must  have  been  a  recognition  of  different  kinds  of 
suffering  and  of  the  need  of  a  corresponding  variety  of  remedial  meas- 
ures. Among  these  healers,  too,  there  doubtless  early  arose,  as  incentive 
to  discrimination,  in  addition  to  the  desire  to  help  and  the  desire  for 
knowledge,  the  desire  to  be  successful  for  the  sake  of  livelihood,  power, 
prestige,  and  other  personal  rewards.  In  the  eft'ort  to  satisfy  these 
desires,  partly  private,  partly  social,  the  art  of  diagnosis  had  its  crude, 
empirical  beginnings.  Listening  to  the  complaints  of  those  who  suf- 
fered, watching  their  behavior,  comparing  the  observations  made  on  a 
given  case  with  those  made  on  others  earlier  in  their  experience,  primi- 
tive healers  gradually  acquired  experience  and  handed  down  their  ob- 
servations, opinions,  beliefs,  and  customs  to  their  successors  (medical 
tradition). 

The  striking  character  of  certain  illnesses  and  accidents  unquestion- 
ably helped  to  determine  the  order  of  development  of  medical 
observation  and  opinion.  Wounds,  hemorrhages,  fractures,  and  disloca- 
tions, large  tumors,  phlegmons,  convulsions,  paralyses,  chills,  fevers, 
anasarca,  deliria,  violent  pains,  blindness,  deafness,  jaundice,  persistent 
vomiting,  madness,  melancholy,  and  other  gross  manifestations  doubt- 
less earliest  attracted  attention;  an  acquaintance  with  these  that  per- 
mitted him  to  recognize  them  when  he  met  them  constituted  the  diag- 
nostic knowledge  of  the  ancient  practitioner.  It  is  easy,  then,  to  under- 
stand why,  in  earlier  times,  external  medicine  should  have  developed 
before  internal  medicine,  and  why  the  observation  of  the  natural  course 
of  disease  should  have  yielded  important  facts  that  bore  upon  prognosis 
long  before  a  therapy  that  could  lay  any  claim  to  rationality  could  be 
applied. 

The  study  of  the  natural  course  of  disease  and  of  prognosis  was 
doubtless  an  inspiration  to  further  diagnostic  discrimination  and  resulted 
in  the  general  growth  of  diagnostic  knowledge.  The  course  and  the 
outcome  were  so  different  in  different  cases  of  hemorrhage,  of  fever, 
and  of  paralysis,  for  example,  that  curiosity  must  early  have  been 
stimulated  to  seek  explanations  by  attempting  an  analysis  of  the  dif- 
ferent kinds  of  hemorrhage,  of  fever,  and  of  paralysis.  The  primitive 
descriptions  of  disease  were,  perforce,  vague  and  indefinite.  The  class 
names  that  were  first  used  in  diagnosis  were  names  of  what  we  now  call 
symptoms  and  signs.     The  groupings  that  the  earlier  diagnosticians 


DEVELOPMENT  OF  CLINICAL  DIAGNOSIS  621 

made  use  of  were  probably  the  best  that  could  be  selected  for  the  pur- 
poses of  their  time;  but  we  can  be  sure  that  then,  as  now,  there  were 
only  a  few  who  recognized  that  groupings  are  conceptual,  and  that  they 
must  be  changed  when  the  purposes  for  which  they  are  wanted  change. 
The  rank  and  file  are,  at  all  times,  prone  to  accept  classes  and  class- 
names  as  given  facts  that  need  no  further  investigation.  The  value  of 
a  class-name  is  to  assemble  (for  convenience  in  making  general  state- 
ments) individuals  that  have  points  of  resemblance  or  "  common  attri- 
butes "  despite  the  fact  that  they  also  differ  from  one  another;  the 
class-name  stands  for  "  unity  in  spite  of  difference."  When,  for  exam- 
ple, diagnosticians  assembled  a  group  of  cases  under  the  class-name 
"  paralysis,"  they  sometimes  forgot  that  the  differences  between  one 
member  of  the  class  and  other  members  of  that  class  might,  for  certain 
purposes,  be  more  important  than  the  resemblances.  Thus,  a  gumma 
pressing  on  the  thoracic  portion  of  the  spinal  cord  causes  paralysis;  a 
metastatic  carcinoma  in  the  same  region  causes  paralysis.  For  the  pur- 
poses of  description,  the  class-name  "  paralysis  "  has  its  value  for  both 
instances;  for  purposes  of  prognosis  and  therapy,  other  class-names 
(syphilis  and  cancer)  are  more  important.  In  other  words,  in  assigning 
an  individual  to  a  class,  the  value  of  the  assignation  depends  upon  the 
aim  or  purpose  we  have  in  view.  We  have  gradually  to  find  out  the 
"  degrees  of  generality  "  that  exist,  for  one  class  possesses  higher  gen- 
erality than  another  if  it  includes  not  only  that  other  but  also  more.  The 
older  logicians  recognized  these  scales  of  generality,  and  arranged  tables 
of  higher  classes  (general)  and  lower  classes  (special)  in  order — the 
so-called  "tree"  of  division  or  classification  (e.g.  Porphyry's  tree). 
And  advance  in  diagnosis  has  resulted  from  discovering  specific  differ- 
ences (differentiae)  between  members  of  general  classes  made  for  cer- 
tain purposes,  and  discovering  features  that  make  assignation  to  other 
classes  that  we  create  for  other  purposes  more  important.  By  examin- 
ing closely  the  members  of  a  class  for  portions  that  for  some  clearly-seen 
purpose  differ  essentially  from  one  another,  diagnostic  thought  moves 
ever  towards  clearer  definition.  This  movement  from  vagueness  towards 
definiteness  is  on  the  one  hand  the  effect,  on  the  other  the  cause,  of  each 
advance  in  the  growth  of  diagnostic  knowledge. 

Now,  it  is  this  movement  of  diagnostic  thought,  impelled  by  the  desire 
for  more  effective  treatment  based  upon  more  accurate  and  ever  more 
definite  knowledge,  that  accounts  for  the  growth  of  the  medical  sciences 
as  a  whole  and  for  the  subdivision  of  diagnosis  itself  into  three  parts 
(pure  science,  applied  science,  and  art).  In  order  that  diagnosis  may 
become  something  more  than  merely  regional  and  external,  a  knowledge 
of  the  interior  of  the  body  and  its  development,  a  knowledge  of  the 


622         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

mind  and  its  development,  and  a  knowledge  of  the  environment  of  the 
body  and  mind,  including  a  knowledge  of  the  modes  of  interpenet ration 
of  associated  minds,  become  important.  Anatomy,  physiology,  pathol- 
ogy, and  psychology  are  the  sons  and  daughters  of  diagnosis,  children 
that,  in  turn,  contribute  lavishly  to  the  parental  larder.  Diagnosis  gradu- 
ally became  internal  as  well  as  external ;  organal,  histological,  cy tological, 
and  chemical  as  well  as  regional ;  functional  and  dynamic  as  well  as  struc- 
tural and  static;  psychic  as  well  as  somatic;  social  and  situational  as 
well  as  personal;  etiological  and  pathogenetic  as  well  as  symptomatic 
and  descriptive.  Diagnosis  has  become  partly  a  pure  science  based  upon 
data  derived  from  a  large  number  of  subsidiary  sciences;  partly  an 
applied  science  in  which  the  utilities  of  the  truths  of  the  pure  science 
are  perceived  and  the  necessary  adjustments  for  realizing  them  are 
made;  and  partly  an  art  in  the  exercise  of  which  practitioners  employ 
more  or  less  skillfully  the  inventions  that  the  applied  science  affords. 

The  Position  and  the  Relationships  of  the 
Science  of  Clinical  Diagnosis 

The  meaning  of  diagnosis  has,  during  the  centuries,  become  grad- 
ually enlarged.  The  term  "  diagnosis  "  came  to  us  through  Latin  from 
the  Greek  dia-,  through,  or  thorough,  and  gignosko,  recognize.  As 
applied  to-day  it  is,  of  course,  attached  to  a  far  more  complex  subject 
than  could  have  been  anticipated  by  those  who  first  used  the  name. 
Through  the  development  referred  to  above,  a  development  that  is  going 
on  in  our  time  more  rapidly  than  ever  before,  a  pure  science,  an  applied 
science,  and  an  art  of  diagnosis  may  be  said  to  have  come  into  existence, 
for  we  now  possess  (i)  laws  and  principles  that  hold  in  diagnosis 
("pure,"  or  "theoretical,"  diagnostic  science),  (2)  perceptions  of  the 
possibilities  of  utility  and  inventions  through  which  the  principles  are 
applied  ("practical,"  or  "applied,"  diagnostic  science),  and  (3)  skill 
and  experience  in  employing  these  inventions  in  practice  (diagnostic 
art). 

The  "  pure  "  science  of  medical  diagnosis  treats  of  the  phenomena 
and  laws  of  disease,  explains  the  processes  by  which  pathological  phe- 
nomena occur,  tracing  each  phenomenon  back  through  a  series  of  ante- 
cedent conditions,  and  inquires  into  the  anatomical,  physiological,  bio- 
logical, chemical,  physical,  psychological,  and  social  causes  of  disease- 
states.  This  "  pure "  science  of  diagnosis,  like  every  other  "  pure " 
science,  is  Interested  in  facts  and  their  regular  occurrence.  It  reasons 
about  the  facts  and  discovers  "  truth,"  but  It  rests  upon  faith,  namely, 
"  faith  that  causation  is  universal,"  faith  that  "  all  effects  have  causes 


SCIENCE  OF  CLINICAL  DIAGNOSIS  623 

and  all  causes  have  effects,"  and  faith  that  "  beneficial  results  will  follow 
the  discovery  of  truth." 

The  progress  of  any  science  is  irregular  and  more  or  less  paroxysmal, 
but  the  general  methods  used  for  making  progress  are  the  same  for  all 
the  sciences.  Progress  in  the  science  of  diagnosis  results  from  the  work 
of  a  huge  army  of  clinical  and  laboratory  investigators,  each  of  whom 
has  his  individual  peculiarities,  has  had  his  own  special  training,  and 
lives  and  works  in  his  own  particular  environment.  It  is  not  strange, 
therefore,  that  even  men  who  are  trying  to  solve  the  same  problem 
should  approach  it  in  different  ways,  should  use  different  methods,  and 
should  attain  to  somewhat  different  results.  Still  the  general  method 
employed  by  all  serious  scientific  research  workers  is  the  same.  A 
problem  is  set;  a  special  technique  suited  to  the  particular  purposes  of 
the  investigator  is  constructed ;  observations  and  experiments  are  made ; 
the  results  are  recorded.  If  these  results  prove  to  be  important,  they, 
and  the  methods  by  which  they  have  been  obtained,  are  published.  Other 
workers,  noticing  the  publication,  try  to  verify  or  to  disprove  the  results, 
using  other  similar  materials  but  working  by  somewhat  different  methods 
in  a  different  environment  with  a  background  of  a  different  natural 
endowment  and  a  different  past  experience.  They  criticize  and  are  led 
through  their  criticisms  to  make  further  observations  and  experiments. 
All  of  the  earlier  results  may  be  disproved  or  all  of  them  may  be 
verified;  more  often,  some  of  the  earlier  results  stand  the  crucial  test 
and  come  to  be  admitted  as  truths  by  everybody,  whereas  others  of  the 
results  fail  to  stand  the  test  and  are  rejected.  Gradually,  the  tested 
and  accepted  results  in  connection  with  special  problems  in  a  number  of 
circumscribed  fields  make  a  considerable  mass  and  attract  the  attention 
of  some  worker  with  a  synthesizing  mind  who  coordinates  the  new 
results  in  comprehensive  papers.  Later,  the  results  thus  coordinated 
get  into  textbooks  and  the  knowledge  is  made  widely  accessible;  the 
achievements  of  the  relatively  few  workers  in  each  circumscribed  field 
can  thus  be  appropriated  by  the  many  who  are  distributed  over  the  whole 
area  of  medical  research  and  medical  practice.  Thus,  though  advances 
in  diagnosis  may  have  been  made  by  fits  and  starts,  the  forward  strides 
have  been  due  to  the  application  of  the  method  of  science. 

The  science  of  medical  diagnosis,  or  science  of  the  thorough  recog- 
nition of  disease,  Is,  like  every  other  true  science,  a  domain  in  which 
phenomena  occur  in  regular  order  as  the  effects  of  natural  or  efficient 
causes,  such  that  a  knowledge  of  the  causes  renders  it  possible  to  predict 
the  effects.  In  the  last  analysis,  the  causes  are  natural  "  forces  " ;  they 
obey  the  Newtonian  laws  of  motion.  The  word  "  law  "  In  science  Implies 
"  uniformity  of  movement."     In  the  sciences  of  mechanics,  astronomy, 


624         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

and  physics,  the  phenomena  can  be,  in  large  measure,  reduced  to  exact 
measurement  and  in  them  the  "  theory  of  units  "  (mass,  space,  time)  is 
easily  applicable.  In  the  more  complex  sciences,  the  phenomena  cannot 
yet  be  reduced  to  exact  measurement,  except  to  a  limited  extent.  We 
believe,  however,  that  exact  laws  do  prevail  in  medical  science  as  well  as 
in  all  natural  domains,  though  our  knowledge  of  these  laws  is  as  yet 
exceedingly  imperfect.  It  is  "  faith  in  the  order  of  the  universe,"  belief 
that  laws  are  uniform  and  invariable  in  the  fields  of  life,  mind,  and 
society  (as  well  as  in  other  cosmic  fields)  that  makes  the  sciences  of 
biology,  psychology,  sociology,  and  medicine  possible.  Social,  psychic, 
and  biotic  phenomena  are  exceedingly  complex,  but  study  of  them  by 
exact  methods  reveals  the  existence  of  uniformities  among  them.  They 
occur  in  order.  They  are  subject  to  law  just  as  rigorously  as  are  the 
phenomena  of  chemistry  and  physics.  To  discover  the  laws  that  health- 
phenomena  and  disease-phenomena  obey,  we  must  use  the  method  of 
science,  the  method  that  has  revealed  to  the  physicist  the  laws  to  which 
heat,  light,  electricity,  and  magnetism  conform.  The  diagnostician  must 
know  in  order  that  he  may  accurately  predict  and  successfully  control. 

A  word  may  be  said  as  to  the  place  of  diagnosis  and  of  the  other 
medical  sciences  in  the  classifications  of  all  the  general  and  special 
sciences  that  have  been  attempted.  The  fundamental  sciences,  as  they 
have  been  arranged  serially  (and  more  or  less  genetically),  are  astron- 
omy, physics,  chemistry,  biology,  psychology,  and  sociology.  As  com- 
plexity increases  in  the  series,  the  degree  to  which  the  phenomena  can  be 
exactly  determined,  what  Comte  called  the  "  positivity,"  decreases. 
Comte  made  each  of  these  coordinate  fundamental  sciences  stand  at  the 
head  of  a  hierarchy  of  sciences  that  can  be  arranged  in  a  logical,  or 
synoptical,  order.  It  is  obvious  that,  if  we  adopted  such  a  classification, 
the  natural  place  for  the  sciences  of  medicine  would,  like  those  of 
technology,  be  within  the  hierarchy  of  which  sociology  is  the  head.* 
Properly  to  understand  the  complex  and  less  exact  clinical  science  of 
diagnosis,  a  comprehensive  grasp  (but  not  necessarily  a  mastery  of  the 
details)  of  all  the  simpler  and  more  exact  sciences  (physiological,  bio- 
logical, chemical,  etc.)  below  it  is  necessary.  Classifications  of  the 
sciences,  imperfect  as  they  are,  do  help  us  to  understand  the  manifold 
relations  of  our  own  science  and  give  useful  pedagogic  hints  for  the 
most  suitable  arrangement  of  curricula. 

To  understand  just  what  diagnosis  is,  and  what  it  is  not,  it  is  neces- 
sary to  determine  its  boundaries,  to  differentiate  it  clearly  from  other 

*  No  classification  of  the  sciences  as  a  whole  can  be  regarded  as  entirely  satis- 
factory. A  very  good  attempt  at  a  more  elaborate  classification  than  the  simple  one 
given  by  Comte  is  that  of  Karl  Pearson.    See  his  "  Grammar  of  Science,"  2  d  ed.,  1900. 


RELATIONS  OF  DIAGNOSIS  AND  PHYSICS  625 

sciences,  and  especially,  perhaps,  from  those  to  which  it  is  most  closely 
related.  "  The  view  or  theory  of  the  relations  of  the  subject  to  other 
subjects  and  to  the  known  world  in  general,  as  distinguished  from  the 
view  or  theory  of  it  as  isolated  or  in  itself,"  has  been  given  as  a  defini- 
tion of  the  "  philosophy "  of  a  subject  as  distinguished  from  its 
"science."  Though  the  distinction  drawn  between  science  and  phi- 
losophy is  now  less  sharp  than  that  formerly  drawn,  there  is  something 
to  be  gained  by  considering  separately  the  philosophy  of  a  science  in 
the  sense  mentioned  above,  namely,  its  relationships,  and  the  definite 
delimitation  of  its  field. 

Relations  of  Diagnosis  and  Physics 

Of  all  the  natural  sciences  to  which  clinical  diagnosis  is  related, 
none  is  more  fundamental  than  the  science  of  physics.  Under  physics 
are  grouped  the  subjects  (excluding  chemistry  and  biology)  that  treat 
of  the  properties  of  matter  and  energy  and  of  the  action  of  the  different 
forms  of  energy  on  matter.  The  conceptions  of  matter  and  energy,  of 
mass  and  motion,  and  of  space  and  time,  dealt  with  by  physics,  lie  at 
the  basis  of  the  scientific  analysis  of  all  natural  phenomena,  including 
those  that  we  deal  with  in  diagnosis. 

The  laws  of  dynamics,  which  deal  with  the  action  of  force  on  bodies 
whether  at  rest  or  in  motion,  hold  for  the  processes  that  go  on  within 
the  human  body,  which  the  diagnostician  studies.  The  prospective 
student  of  diagnosis,  who  in  his  early  education  gains  some  acquaintance 
with  theoretical  mechanics,  not  only  acquires  conceptions  that  aid  him 
in  the  understanding  of  the  problems  of  the  pre-clinical  and  clinical 
medical  sciences  but  also,  through  dealing  with  these  ideal  representa- 
tions, secures  a  training  in  abstract  thought  that  should  be  helpful  to 
him  in  the  whole  of  his  subsequent  career.  The  methods  and  principles 
of  applied  mechanics,  the  subject  that  deals  with  the  theory  of  structures 
and  with  the  theory  of  machines,  are  likely,  as  the  medical  sciences  grow, 
to  be  ever  more  applicable  to  the  solution  of  problems  connected  with 
the  structures  and  mechanisms  of  the  human  machine. 

That  the  study  of  the  physics  of  heat,  light,  sound,  electricity,  and 
magnetism  stand  in  intimate  relation  to  the  study  of  the  functions  of 
the  human  body  in  both  normal  and  abnormal  conditions,  goes  without 
saying.  The  diagnostician  could  not  view  intelligently  the  phenomena 
of  fever  and  of  metabolism  if  he  were  unacquainted  with  the  effects 
produced  by  heat  on  material  bodies,  with  the  laws  of  transference  of 
heat  and  with  the  laws  that  govern  transformation  of  heat  into  other 
kinds  of  energy.  Thermometry  and  calorimetry  are  simple  and  direct 
applications  of  physics  to  clinical  diagnosis.     And  how  unsatisfactory 


626         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

would  be  the  work  of  the  general  as  well  as  of  the  ophthalmic  diagnos- 
tician who  had  not  studied  the  physics  of  light,  the  laws  of  its  recti- 
linear propagation,  of  its  reflection  and  of  its  refraction,  and  the  relations 
of  light  to  the  phenomena  of  vision  and  of  color  perception!  In  the 
construction  of  instruments  of  precision  for  diagnostic  work,  applied 
optics  has  made  a  very  great  contribution.  To  recall  this  fact  vividly 
to  mind,  I  need  refer  only  to  the  microscope,  the  polariscope,  the  photo- 
graphic camera,  the  ophthalmoscope,  the  speculum,  the  cystoscope,  the 
bronchoscope,  the  sigmoidoscope,  and  the  refractometer,  and  the  uses 
to  which  they  have  been  put  in  clinical  diagnosis.  The  manifold  appli- 
cations of  mirrors  and  lenses  of  different  sorts  in  clinical  diagnosis 
nowadays  are  contributions  of  optics  that  command  the  gratitude  of 
every  worker  in  the  field  of  clinical  diagnosis.  Almost  as  important, 
too,  are  the  applications  of  the  physics  of  sound  to  the  work  of  clinical 
inquiry.  The  art  of  auscultation  in  physical  diagnosis  can  be  prac- 
ticed only  inefficiently  by  one  who  is  ignorant  of  the  physical  phenomena 
that  correspond  to  the  loudness,  the  pitch,  and  the  quality  of  sounds. 
Instruments  of  precision  like  the  stethoscope,  the  microphone,  the  phono- 
cardiograph,  the  tuning  fork,  the  continuous  tone  series,  and  the  noise 
apparatus  are  direct  contributions  of  applied  phonetics  to  clinical  diag- 
nosis. It  is  astonishing,  too,  how  various  the  applications  of  electrical 
science  to  diagnostic  technic  have  been.  In  recent  years,  these  have 
grown  very  rapidly.  The  testing  of  the  functions  of  muscles  and 
nerves  by  the  faradic  current  and  by  the  galvanic  current  were  early 
methods  of  employing  electrical  science  in  the  service  of  medical  diag- 
nosis. The  uses  of  electricity  for  the  illumination,  when  instruments  of 
inspection  are  employed  on  clinical  examination,  have  been  more 
recently  recognized  and  these  modes  of  applying  electricity  in  medical 
practice  have  become  ever  more  important  and  helpful  to  the  diagnos- 
tician and  therapeutist.  Furthermore,  the  applications  of  electricity 
in  roentgenological  work  are  now  manifold  and  by  no  means  simple,  as 
every  expert  X-ray  worker  sooner  or  later  learns.  A  general  knowledge 
of  heat,  light,  sound,  electricity,  and  magnetism  is,  therefore,  obviously 
essential  for  good  work  in  medical  diagnosis. 

One  of  the  most  important  influences  of  the  study  of  physics  on  the 
science  of  diagnosis  is  the  understanding  that  the  former  subject  gives 
of  the  different  forms  of  energy,  and  of  the  law  of  conservation  of 
energy  during  transformation,  as  they  concern  the  human  body.  When 
we  recall  that  stimuli  are,  in  the  last  analysis,  physical  agencies,  namely 
forms  of  energy  that  excite  or  depress  the  several  functions  of  the  living 
body,  we  realize  how  important  a  role  applied  physics  must  ultimately 
play  in  physiology  and,  accordingly,  in  diagnosis.    The  studies  of  direc- 


RELATIONS  OF  DIAGNOSIS  AND  CHEMISTRY       627 

tive  stimulation  in  lower  forms  of  life  (phototaxis,  chemotaxis,  thermo- 
taxis,  galvanotaxis,  etc.)  show  us  clearly  certain  of  the  directions  that 
research  must  take  if  we  are,  later  on,  to  understand  more  clearly  than 
we  do  now  the  activities  of  the  cellular  constituents  of  the  human  body 
in  health  and  in  disease. 

As  diagnostic  work  grows  gradually  more  precise,  it  makes  ever 
greater  use  of  certain  standards  of  measurement  that  we  owe  to  the 
physicists.  Quantitative  work  in  physics  has  been  greatly  facilitated  by 
the  selection  for  each  measurable  magnitude  of  a  physical  unit,  or 
standard  of  reference;  with  the  aid  of  these  units,  other  similar  quan- 
tities can,  by  comparison,  be  numerically  defined.  Fortunately,  since 
physicists  have  become  convinced  that  one  form  of  physical  energy  is 
convertible  into  another  and  that  the  change  takes  place  according  to 
definite  laws,  it  has  been  possible  to  coordinate  these  several  physical 
units.  The  most  fundamental  units  are  those  of  length,  mass,  and  time — 
the  centimeter,  the  gram,  and  the  second  (hence  the  name  CGS-system 
of  units).  All  other  physical  units  of  measurement  take  account  of  these 
fundamental  notions  of  length,  mass,  and  time.  In  mechanics  the  unit 
of  force  is  the  dyne,  the  unit  of  work  is  the  erg,  the  unit  of  power  is 
the  watt,  the  unit  of  energy  is  the  joule.  In  the  physics  of  heat  the  unit 
of  heat  is  the  calorie.  In  electricity  the  unit  of  resistance  is  the  ohm,  the 
unit  of  current  is  the  ampere,  the  unit  of  electromotive  force  the  volt, 
etc.  These  units  are  coming  ever  more  into  use  in  clinical  diagnostic 
work.  Their  general  adoption  in  scientific  work  is  a  forcible  example 
of  the  fundamental  relation  in  which  physics  stands  to  all  the  more 
complex  sciences  of  nature. 

The  physical  sciences,  then,  including,  as  they  do,  dynamics,  me- 
chanics, the  physics  of  heat,  light,  sound,  electricity,  and  magnetism, 
energetics,  and  the  setting  up  of  units  to  be  used  as  standards  of  meas- 
urement, are  seen  to  be  essential  as  a  part  of  the  basis  upon  which  a 
science  of  diagnosis  can  be  built.  Medical  educators  have  been  wise, 
therefore,  in  making  knowledge  of  the  theory  and  some  skill  in  the  use 
of  the  practical-technical  methods  of  physics  a  prerequisite  to  the  study 
of  medicine  and  of  diagnosis. 

Relations  of  Diagnosis  and  Chemistry 

The  science  of  chemistry  stands  in  almost  as  fundamental  a  relation- 
ship to  the  science  of  diagnosis  as  does  the  science  of  physics.  Chem- 
istry has  to  do  with  the  study  of  the  composition  of  substances  and  of 
the  changes  in  composition  that  substances  undergo,  whereas  physics, 
which  we  have  just  considered,  studies  rather  the  properties  of  sub- 
stances.   In  physical  chemistry,  in  process  of  development,  we  see  a  new 


628  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

science  that  attempts  to  correlate  the  physical  properties  of  substances 
with  their  chemical  composition.  Our  knowledge  of  the  composition 
of  the  substances  in  the  cells  and  in  the  fluids  of  the  human  body  has 
already  become  very  important  for  the  student  of  the  science  of  diag- 
nosis. Indeed,  it  could  scarcely  be  otherwise  since  the  fact  of  the  life 
of  the  human  body  is  metabolism.  The  living  substance  is,  on  the  one 
hand,  ever  undergoing  decomposition  (dissimilation  or  catabolism),  and, 
on  the  other,  is  ever  undergoing  reconstruction  (assimilation  or  anabo- 
lism).  With  the  exact  composition  of  the  most  complex  types  of 
chemical  substances  existing  in  the  body — the  hypothetical  biogens — we 
are  as  yet  unfamiliar,  but  of  the  importance  in  their  composition  of  the 
long  chains  of  amino-acids  known  as  proteins  we  have  now  become 
convinced.  Physiologists  and  physiological  chemists  have  already  gone 
far  toward  demonstrating  to  us  how  the  foods  taken  into  the  body  are 
changed  in  order  that  suitable  building-stones  may  be  available  for  the 
construction  of  the  complex  biogen-molecules  of  protoplasm,  and  they 
are  also  revealing  to  us  the  various  stages  in  the  degradation  processes 
through  which  these  biogens  form  secretions  and  excretions  as  end- 
products  of  the  body  metabolism.  The  fascinating  studies  that  deal  with 
the  morphological  changes,  with  the  chemical  changes,  and  with  the 
energy  changes  that  accompany  the  body  metabolism  were  growing 
yearly  more  numerous  before  the  outbreak  of  the  great  war;  they  will 
doubtless  be  resumed  with  even  greater  vigor  now  that  the  war  is  over 
and  the  nations  can  again  settle  down  to  the  leisurely  and  undisturbed 
cultivation  of  medical  science.  The  principles  and  the  practical-technical 
methods  of  chemistry  are  now  a  part  of  the  stock-in-trade  of  the  well- 
equipped  student  of  diagnosis. 

If,  then,  the  modern  diagnostician  needs  to  be  tolerably  familiar  with 
the  principles  and  the  methods  of  chemical  science,  his  preparatory 
studies  should  include  inorganic  chemistry,  organic  chemistry,  analytical 
chemistry,  and  physical  chemistry.  The  medical  diagnosis  of  to-day 
makes  extensive  use  of  the  principles,  of  the  terminology,  and  of  the 
machinery,  of  all  these  subdivisions  of  chemistry.  The  work  of  diag- 
nosis in  the  clinical  laboratory  demands  considerable  practical  acquaint- 
ance with  the  apparatus  and  the  technique  of  chemical  manipulations. 
In  the  clinical  investigation  of  metabolism,  especially,  a  knowledge  of 
chemistry  and  an  acquaintance  with  chemical  methods  is  essential.  I 
need  refer  only  to  the  chemistry  of  the  proteins  and  of  their  derivatives, 
and  its  applications  to  metabolism  in  the  renal  diseases  and  in  the  amino- 
acid  diatheses;  to  the  chemistry  of  the  carbohydrates  and  its  applica- 
tions to  metabolism  in  diabetes  mellitus  and  allied  disturbances;  to  the 
chemistry  of  the  fats  and  its  relations  to  obesity  on  the  one  hand,  and 


RELATIONS  OF  DIAGNOSIS  AND  BIOLOGY  629 

to  acidosis  on  the  other;  to  the  chemistry  of  the  mineral  substances  in 
the  body  and  its  relations  to  the  metabolism  in  rickets,  in  osteomalacia, 
and  in  tetany;  to  the  chemistry  of  the  nucleins,  purins,  and  pyrimidins 
and  its  relations  to  the  metabolism  in  gout;  and,  finally,  to  the  as  yet 
little  known  chemistry  of  the  vitamins  and  its  relations  to  the  metabolism 
in  beri-beri  and  in  other  diseases  in  which  there  is  believed  to  be  vitamin 
deficiency.  If  I  were  to-day  a  student  in  my  teens,  looking  forward  to 
the  study  of  diagnosis  and  therapy,  and  could  realize  at  that  age  as  I 
do  now  the  fundamental  importance  of  physical  and  chemical  science 
for  the  future  of  the  biological  and  medical  sciences,  I  should  make  a 
great  effort  to  become  firmly  grounded  in  the  different  branches  of 
physics  and  chemistry,  securing  also  sufficient  training  in  mathematics 
to  permit  of  their  higher  study.  Young  students  of  to-day  who  will 
avail  themselves  of  this  hint  before  going  on  to  the  study  of  the  bio- 
logical and  medical  sciences  will,  I  feel  sure,  be  richly  rewarded  when 
they  become  the  diagnosticians  and  therapeutists  of  twenty  years  from 
now.  The  time  and  energy  expended  in  the  acquisition  of  sound  and 
thorough  physical  and  chemical  experience  as  a  preliminary  to  medical 
study  could  scarcely  be  better  employed. 

Relations  of  Diagnosis  and  Biology 

The  relationship  of  the  science  of  diagnosis  to  the  science  of  biology 
is  obvious  and  yet  there  should  be  no  confusion  or  overlapping  as  regards 
their  respective  fields.  As  abstract  sciences,  biology  deals  with  the 
laws  of  life,  diagnosis  with  the  laws  of  the  recognition  of  health  and  of 
disease  in  living  organisms.  Each  science  is  important  for  the  other 
though  each  differs  from  the  other.  From  biology  we  learn  that  the 
tendency  of  evolution  is  to  "  transfer  the  maximum  amount  of  inorganic 
matter  to  the  organized  state  "  as  a  part  of  the  general  process  of  storing 
cosmical  energy.  The  most  complex  chemical  combination  known  is 
protoplasm,  the  "  physical  basis  of  life."  In  biotic  organization,  the  unit 
is  the  cell,  a  very  complex  structure  when  compared  with  the  relatively 
simple  constitution  of  protoplasm.  Biology  treats  of  unicellular  and 
multicellular  organisms,  of  their  structures  and  functions,  of  their 
origin,  growth,  and  destiny.  It  reveals  the  advantages  of  living  beings 
as  organized  mechanisms  for  the  storage  and  expenditure  of  energy. 
It  studies  reactions  between  organisms  and  their  environment  and  shows 
how  capacity  for  suitable  adjustment  makes  for  success  and  survival, 
and  how  inability  adequately  to  adjust  leads  to  failure  and  extinction. 
It  explains  the  origin  of  anatomical  structures  and  the  relations  of 
structures  to  functions.  It  discovers  that  at  certain  stages  of  biotic 
organization  feeling  becomes  important  for  the  preservation  of  life,  that 


630         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

pleasure  and  pain  are  conditional  to  the  existence  of  plastic  organisms, 
and  that,  out  of  sentiency,  mind  develops.  Knowing,  feeling,  and 
striving  become  ever  more  important  factors  in  the  living  of  higher 
organisms.  Some  kinds  of  structure,  some  varieties  of  function,  and 
some  modes  of  feeling,  striving,  and  knowing  are  advantageous  to 
organisms  and  make  for  their  survival;  others  are  disadvantageous  and 
lead  to  disease  or  death  of  individuals  and  of  species.  Evolution, 
heredity,  variation,  adaptation,  and  selection,  as  studied  by  the  biologist, 
are  all  important  as  building-stones  in  the  foundation  of  a  science  of 
diagnosis. 

The  relation  of  diagnosis  to  one  of  the  special  biological  sciences, 
anthropology,  may  be  considered  from  two  points  of  view.  The  student 
of  diagnosis  looks  upon  the  science  of  anthropology  as  a  part  of  the 
foundation  for  the  science  of  diagnosis,  whereas  the  anthropologist  will 
look  upon  that  part  of  diagnosis  that  deals  with  the  recognition  of  health 
and  of  disease  in  man  as  belonging  to  the  science  of  man.  Undoubtedly, 
the  two  sciences  overlap  and  the  facts  and  phenomena  of  each  are  impor- 
tant for  the  other  science.  Anthropology  as  a  descriptive  science  is  really 
a  branch  of  zoology.  A  knowledge  of  the  peculiarly  human  character- 
istics, which  anthropology  supplies,  is  too  often  disregarded  by  students 
of  the  science  of  diagnosis  who  transfer,  without  criticism,  conclusions 
drawn  from  observations  upon  experimental  animals  directly  to  the 
human  sphere.  Of  the  different  departments  of  anthropology,  it  is 
somatology  (dealing  with  man's  physical  constitution)  and  technology 
(dealing  with  man's  products,  material  and  institutional)  that  are  most 
important  for  the  student  of  diagnosis.  Among  the  institutions  man  has 
produced  are  languages,  customs,  governments,  religions,  industries,  art, 
and  literature.  How  inadequate  would  be  the  work  of  the  student  of 
diagnosis  who  lacked  familiarity  with  these  achievements  of  man !  Both 
the  "  natural  history  of  man  "  and  the  "  history  of  culture  "  supply  data 
that  are  essential  for  the  construction  of  a  science  of  diagnosis. 

The  biological  sciences  deal,  then,  with  living  organisms,  and  pa- 
tients who  consult  physicians  are  living  organisms  that  conform  to 
biological  laws.  All  the  special  biological  sciences,  including  (i)  Mor- 
phology, which  deals  with  the  statical  aspects  of  the  organic  world,  or 
with  the  structure  of  living  organisms,  (2)  Physiology,  which  deals 
with  the  dynamical  aspects  of  the  same  world,  or  with  the  properties, 
processes,  and  functions  of  living  organisms,  (3)  Distribution,  which 
deals  with  the  number  of  organisms  of  different  kinds  in  different  parts 
of  the  world,  and  (4)  Evolution,  or  Etiology,  which  deals  with  the  nat- 
ural history  of  the  cosmos,  in  as  far  as  it  concerns  organic  beings,  can 
contribute  to  the  science  of  diagnosis.     That  training  in  the  principles 


RELATIONS  OF  DIAGNOSIS  AND  PSYCHOLOGY     631 

and  methods  of  the  biological  sciences  should,  like  similar  training  in  the 
sciences  of  physics  and  chemistry,  be  now  regarded  as  an  essential  pre- 
requisite to  the  study  of  medicine  and  diagnosis  seems,  therefore,  a 
reasonable  opinion  for  the  medical  educator  to  hold. 

Relations  of  Diagnosis  and  Psychology 

Turning  to  another  subject,  it  is  surprising  how  little  attention  has 
been  paid  by  those  who  frame  pre-medical  curricula  to  the  importance  of 
the  relations  of  the  science  of  psychology  to  the  science  of  diagnosis. 

Psychology,  as  the  science  of  mind,  embraces  not  only  the  phenomena 
of  "  intellect "  but  also  those  of  the  "  affections "  and  those  of  the 
"  will."  Students  of  human  psychology  study  the  knowing,  the  feeling, 
and  the  striving  of  man.  Biology  has  shown  us  that  feelings  of  pleasure 
induce  lower  animals  to  look  for  food  and  to  eat  it  and  to  perform  the 
acts  that  reproduce  their  kind,  whereas  feelings  of  pain  lead  them  to 
make  efforts  to  escape  from  enemies  and  from  other  dangers.  Among 
higher  animals,  the  knowing  element  became  ever  more  helpful  to  the 
feeling  and  the  striving  elements  of  mind  in  attaining  the  purposes  of 
the  organism.  Man  is  the  most  highly  favored  of  all  living  creatures 
in  this  respect  and  by  virtue  of  his  intellect  has  not  only  obtained 
dominion  over  other  forms  of  life,  but  has  also  become  the  conqueror 
of  the  physical  forces  of  nature.  Feeling  is  dynamic;  intellect  is  direc- 
tive; the  will  is  an  activity  of  purposive  behavior  that  is  determined  by 
feeling  and  intellect. 

In  the  animal  series,  the  intellect  seems  to  have  developed,  at  first, 
as  a  means  of  increasing  agreeable  feeling,  of  overcoming  obstacles  to 
the  satisfaction  of  desires.  The  "  knowing  "  element  gradually  became 
a  most  important  servant  of  the  "  feeling  "  and  "  striving  "  elements  of 
the  mind.  The  human  pleasures  include  the  realization  of  certain  ob- 
jective ends — the  nutritive,  the  reproductive,  the  esthetic,  the  emo- 
tional, the  moral,  and  the  intellectual.  The  desire  for  self-realization 
and  to  obtain  pleasure  ("  lower  "  or  "  higher  ")  is  the  motive  to  effort. 
The  intellect  is  to  be  looked  upon  as  a  directive  agent  to  guide  the 
organism  in  the  achievement  of  its  purposes,  that  is,  in  the  satisfaction 
of  its  desires,  and  in  the  fulfilling  of  all  its  capacities.  It  manifests  itself 
in  foresight,  cunning,  shrewdness,  sagacity,  wisdom,  tact,  ingenuity, 
inventiveness,  art,  science,  and  philosophy. 

The  psychologist  observes  and  studies  his  own  consciousness  and 
the  behavior  of  men  and  of  animals,  and  builds  up  his  science  upon  the 
basis  of  the  facts  thus  accumulated.  He  desires  to  understand  and  to 
explain  his  own  behavior  and  that  of  other  men  and  of  animals.  Knowl- 
edge of  consciousness  and  of  behavior  will,  he  believes,  yield  the  power 


632  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

to  guide  and  control  behavior.  He  defines  behavior  as  the  manner  in 
which  an  organism  possessing  mind  conducts  itself  in  the  active  pursuit 
of  its  own  welfare  and  in  the  effort  to  reach  its  own  ends  or  to  effect 
its  own  purposes.  By  studying  himself  and  observing  the  phenomena 
of  his  own  consciousness  and  his  own  behavior  (as  he,  himself,  thinks 
and  feels  and  strives),  he  deepens  his  understanding  of  the  behavior  of 
all  living  things  and  draws  conclusions  regarding  the  consciousness  he 
believes  they  must  possess  when  they  exhibit  behavior.  By  systematic 
studies  of  this  sort  the  laws  of  mind  are  established. 

In  analyzing  and  describing  the  stream  of  his  own  consciousness, 
the  psychologist  meets  with  very  great  difficulties  and  the  overcoming 
of  these  constitutes  an  important  part  of  his  problem.  He  designates 
the  knowing  aspect  of  mind  as  "  cognitive,"  the  feeling  aspect 
as  "  affective,"  and  the  striving  as  "  conative."  He  seeks  to  explain 
both  what  goes  on  in  consciousness  (and  the  accompanying  behavior)  on 
the  basis  of  the  "  constitution  "  or  the  "  structure  "  of  the  mind,  as  it 
develops  during  the  life  of  the  organism,  a  development  that  is  deter- 
mined partly  by  heredity  and  partly  by  environmental  influences  that 
favor  or  prevent  the  realization  of  the  various  hereditary  possibilities. 
He  conceives  of  the  mind  as  constituted  of  a  large  number  of  "  mental 
dispositions,"  which  form  organized  systems.  The  totality  of  cognitive 
dispositions  he  speaks  of  as  the  "  knowledge  "  possessed  by  the  mind ; 
the  totality  of  affective  and  conative  dispositions  he  refers  to  as  the 
"  character  "  of  the  individual.  Acquaintance  with  the  knowledge  and 
character  of  a  person  gives  the  clue  to  his  conduct  in  a  given  situation. 
Despite  the  difficulties  of  analysis  and  description,  psychologists  are 
gradually  arriving  at  conceptions  that  are  helpful  both  for  theory  and 
practice. 

Now,  the  science  of  diagnosis  is  very  largely  dependent  upon  ob- 
servation of  the  behavior  of  patients  and  necessitates  inquiry  into  their 
mental  states  in  their  cognitive,  affective,  and  conative  aspects.  Most 
physicians,  whether  or  not  they  have  had  any  academic  training  in 
psychology,  acquire  a  certain  power  of  estimating  intellectual  capacity 
and  of  recognizing  types  of  character.  For  the  higher  reaches  of  diag- 
nosis, however,  a  much  fuller  acquaintance  with  the  laws  of  mind  and 
the  phenomena  of  human  behavior  than  can  be  obtained  without  special 
training  in  psychology  is  requisite.  Diagnostic  science  and  the  art  of 
diagnosis  are  now  being  rapidly  promoted  by  men  who  have  been  thor- 
oughly trained  in  psychology  as  a  whole  or  in  one  or  more  of  its 
branches.  A  larger  acquaintance  with  the  psycholog}'-  of  the  normal 
human  adult,  with  the  psychology  of  animals,  with  the  psychology  of 
children,  with  the  individual  psychology  that  deals  with  the  peculiarities 


RELATIONS  OF  DIAGNOSIS  AND  SOCIOLOGY       633 

of  individual  minds,  with  abnormal  psychology,  and  with  the  social 
psychology  that  studies  the  folk-mind,  the  crowd-mind,  and  the  group- 
mind,  and  their  influences  upon  individual  minds  through  the  processes 
of  suggestion,  sympathy,  imitation,  and  interpenetration,  will  doubtless, 
before  long,  be  regarded  as  an  essential  part  of  the  equipment  of  the 
earnest  student  of  diagnosis. 

Relations  of  Diagnosis  and  Sociology 

We  come  next  to  the  kinship  of  diagnosis  and  sociology.  It  is  not 
easy  sharply  to  separate  sociology  from  psychology;  social  psychology 
is  a  link  that  joins  these  two  sciences.  In  studying  psychology,  now- 
adays, the  prospective  student  of  diagnosis  learns,  as  has  just  been  said, 
of  the  importance  of  the  crowd-mind  or  "  mass-mind  "  exhibited  by 
large  masses,  and  of  the  group-mind  that  is  manifested  by  smaller  asso- 
ciations in  every  highly  organized  human  society.  He  studies  the  prin- 
ciples of  collective  thinking,  collective  feeling,  and  collective  acting,  and 
he  makes  an  effort  to  observe  the  influence  of  the  social  milieu  upon  the 
development  of  the  individual  mind.  But  the  science  of  sociology  itself 
is  also  closely  related  to  the  science  of  diagnosis,  and  a  fairly  compre- 
hensive grasp  of  its  methods  and  principles  should  be  acquired  by  those 
who  expect  to  study,  and  to  practice,  diagnosis.  Diagnosis  has  to  deal 
with  the  recognition  of  "  disease  "  in  individuals,  but  these  individuals 
are  members  of  social  groups.  To  understand  an  individual  thoroughly 
one  must  knov/  much  about  the  social  groups  to  which  he  belongs  and 
their  origin  by  ascent  or  descent.  A  knowledge  of  sociology  should 
therefore  be  helpful  to  the  student  and  practitioner  of  diagnosis. 

Sociology,  the  science  of  society,  studies  the  structure,  functions,  and 
genesis  of  the  social  body,  just  as  anatomy,  physiology,  embryology,  and 
psychology  study  the  individual  organism.  It  discovers  what  it  is  in 
man's  nature  that  induces  him  to  associate  himself  with  others;  what 
the  effects  of  association  are  upon  his  interests,  his  feelings,  his  emo- 
tions, his  desires,  and  his  acts;  what  purposes  association  and  coopera- 
tion subserve  and  what  means  are  adopted  for  favoring  them;  what 
relations  become  established  among  men  as  a  result  of  different  kinds  of 
^g'gregation  and  cooperation;  and  what  influence  these  relations  exert 
upon  the  thought,  the  feelings,  and  the  behavior  of  man.  Sociologists 
like  J.  S.  Mill,  A.  Comte,  and  Lester  Ward  have  traced  the  broad  out- 
lines of  the  science  and  a  host  of  workers  are  filling  in  the  details.  The 
data  of  sociology  are  drawn  from  a  large  number  of  special  social 
sciences  (ethnography,  ethnology,  technology,  archeology,  demography, 
history,  economics,  jurisprudence,  politics,  and  ethics) ;  these  data  form 
the  basis  of  the  reasoning  and  the  generalizations  of  the  more  general 


634         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

science.  The  forces  studied  by  the  sociologist  are  psychic;  they  consist 
of  human  motives,  the  unsatisfied  appetites  and  desires  of  men.  These 
forces  are  preservative,  reproductive,  esthetic,  moral,  and  intellectual — in 
other  words,  the  "  forces  of  individual  preservation,"  the  "  forces  of 
race  continuance,"  and  the  "  forces  of  race  elevation."  Feeling  is  the 
dynamic  agent  in  society  and  intellect  is  the  directing  agent.  Resulting 
from  the  collision  of  social  forces,  states  of  approximate  equilibrium 
occur  among  them,  and  social  structures  (including  the  family,  the  clan, 
the  tribe,  the  state,  the  church,  and  other  voluntary  associations)  and 
social  institutions  (including  marriage,  customs,  language,  codes,  reli- 
gions, arts,  literatures,  and  sciences)  arise.  These  structures  and  insti- 
tutions, while  relatively  stable,  are  constantly  undergoing  change; 
though  there  is  at  every  time  a  social  order,  there  is  at  all  times  some 
social  progress,  and  this  progress  is  described  by  the  sociologist  as  partly 
the  result  of  an  unconscious  evolution  (social  genesis),  partly  the  result 
(and  increasingly  so  now)  of  the  conscious  application  of  the  intellect 
as  a  guide  to  human  desires  in  avoiding  obstacles  to  their  satisfaction 
(individual  and  collective  telesis).  Knowledge  of  these  social  structures 
and  functions  and  of  their  evolution,  therefore,  constitutes  the  science 
of  sociology.  None  of  the  better  diagnosticians  of  our  time  is  likely  to 
underestimate  the  importance  for  his  own  science  of  a  knowledge  of 
society,  of  social  structures,  of  social  institutions,  or  of  social  functions. 
For  the  physician  is  constantly  called  upon,  nowadays,  to  recognize  in 
his  patients  states  in  which  there  is  maladjustment  of  the  individual  to 
his  environment,  states  in  which  the  reciprocal  relations  of  the  indi- 
vidual and  of  the  social  groups  to  which  he  belongs  are  unsatisfactory, 
states  that  cannot  be  properly  understood  or  adequately  modified  by  a 
therapeutic  regimen  when  the  individual  is  studied  alone  without  con- 
comitant consideration  of  the  group,  or  groups,  of  socii  to  which  he 
belongs.  The  prospective  diagnostician  should,  therefore,  receive  suf- 
ficient training  in  the  science  of  sociology  and  sHould  familiarize  himself 
with  the  laws  of  association  and  with  the  subtle  psychic  processes  of 
interpenetration  that  characterize  the  activities  of  concrete  groups. 

Relations  of  Diagnosis  to  the  Preclinical  Medical  Sciences 

Though  some  acquaintance  with  the  sciences  of  physics,  chemistry, 
biology,  anthropology,  psychology,  and  sociology,  including  ethics  and 
politics,  is,  as  has  been  emphasized  above,  highly  desirable  as  preparatory 
experience  for  the  student  of  the  science,  and  for  the  practitioner  of 
the  art,  of  diagnosis,  a  still  more  comprehensive  training  is  necessary  in 
certain  distinctively  medical  sciences,  namely,  in  a  group  of  sciences 
intermediate  between  the  fundamental  sciences  above  referred  to  and 


DIAGNOSIS  AND  PRECLINICAL  MEDICAL  SCIENCES   635 

the  clinical  sciences  of  diagnosis  and  therapy.  This  intermediate  group 
of  sciences,  training  in  which  is  indispensable  for  the  prospective 
clinician,  is  usually  taught  in  the  first  two  years  of  the  course  in  the 
medical  school;  these  sciences  we  may  include  under  the  general  name 
of  preclinical  medical  sciences.  This  group  includes  several  sub- 
groups: (i)  an  anatomical  sub-group  (gross  human  anatomy,  micro- 
scopic anatomy,  histology,  cytology,  and  embryology);  (2)  a  physio- 
logical sub-group  (general  and  special  physiology,  physiological  chem- 
istry, and  pharmacology);  and  (3)  a  pathological  sub-group  (general 
pathology,  special  pathological  anatomy,  and  histology,  bacteriology, 
parasitology,  immunology,  psychopathology,  and  social  pathology). 
These  preclinical  sciences  were  largely  developed  in  the  first  place  by 
diagnosticians  (as  postclinical  sciences),  because  their  development  was 
necessary  for  the  growth  of  diagnosis  and  therapy,  but  as  knowledge 
has  grown  and  technique  has  become  ever  more  complex,  they  have  come 
to  be  cultivated  as  sciences  for  their  own  sake  by  men  who  devote  their 
whole  time  and  energies  to  the  single  provinces;  and  they  are  now 
taught,  and  should  be  taught  (as  far  as  developed),  as  prerequisite  to 
work  in  diagnosis.  The  facts  and  principles  of  these  preclinical  sciences 
supply  data  that  are  necessary  as  a  basis  for  the  science  of  diagnosis. 
It  is  essential  that  the  scientific  diagnostician  shall  himself  have  had 
a  general  training  in  the  methods  and  principles  of  each  of  these  pre- 
clinical medical  sciences  and  that  he  shall  have  acquired  such  a  com- 
prehensive grasp  of  them  as  will  permit  him,  first,  to  keep  pace  with 
their  progress  during  his  lifetime,  and,  secondly,  to  make  applications 
of  them  in  any  direction  that  will  be  helpful  to  his  own  science  and  art. 
It  must  be  emphasized,  however,  that  the  problems  of  the  pre- 
clinical medical  sciences,  though  closely  related  to  the  problems  of  the 
science  of  diagnosis,  are  by  no  means  identical  with  them.  There  is 
much  overlapping,  but  it  is  desirable  that  the  purposes  of  each  of  the 
sciences  should  be  kept  clearly  in  view  by  those  who  represent  it.  The 
anatomist  should  work  at  the  problems  of  his  science  for  their  own 
sake,  for  the  sake  of  discovering  facts  and  truths  regarding  the  form 
and  genesis  of  the  structures  in  organisms,  and  especially  in  the  human 
organism,  without  special  reference  to  their  applicability  in  the  science 
of  diagnosis.  It  is  the  business  of  the  investigator  in  the  science  of 
diagnosis  to  make  the  application  of  the  facts  and  truths  of  the  ana- 
tomical sciences  and  their  methods  to  the  solution  of  diagnostic  problems. 
The  same  is  true  as  regards  the  physiological  sub-group  of  the  pre- 
clinical medical  sciences.  It  holds  even  for  the  pathological  sub-group, 
which  many  would  look  upon  as  an  integral  part  of  the  science  of 
diagnosis;  but  the  aims,  purposes,  and  methods  of  the  representatives 


636         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

of  the  special  sciences  of  pathological  anatomy,  pathological  physiology, 
and  bacteriology  are,  and  should  be,  somewhat  different  from  the  aims, 
purposes,  and  methods  of  the  representatives  of  clinical  diagnosis. 
Closely  related  as  the  clinical  and  preclinical  medical  sciences  are,  they 
are  still  separate  and  distinct,  and  much  is  gained  for  both  groups  by 
the  maintenance  of  this  separation  and  distinction. 

Each  science  will  help  its  kindred  sciences  most  by  defining  strictly 
the  limits  of  its  province,  and  cultivating  industriously,  intensively,  and 
conscientiously  its  own  fields  within  that  province.  The  clinician  must 
not  expect  the  anatomist,  the  physiologist,  and  the  pathologist  to  leave 
their  own  special  tasks  to  solve  his  diagnostic  problems  for  him,  nor 
should  the  worker  in  clinical  diagnosis  be  expected  by  his  preclinical 
colleagues  to  neglect  the  crops  on  his  own  acreage  by  yielding  to  the 
temptation  to  till  promising  neighboring  fields.  When  special  needs  are 
felt  and  lead  to  a  division  of  work,  dormant  capacities  are  aroused  and 
new  powers  are  called  into  being.  The  differentiation  of  purposes  and 
of  labor  is  one  of  the  most  powerful  influences  for  increasing  the  range 
of  intellectual  activities  and  for  stimulating  their  development. 

In  diagnosis  itself,  the  field  is  so  large  that  no  single  person  can 
expect  to  work  equally  well  in  all  parts  of  it.  A  division  of  labor  in 
diagnosis,  partly  methodological  and  partly  regional  and  systematic,  has 
proved  profitable,  as  in  science  at  large.  As  evidences  of  this  division 
we  find  diagnostic  workers  distributing  themselves  more  or  less  ( i )  ac- 
cording to  the  methods  they  employ  (applied  physics,  applied  chemistry, 
applied  biology,  applied  psychology,  applied  sociology,  applied  physi- 
ology, applied  pathology,  etc.)  and  (2)  according  to  the  systems  and 
regions  they  especially  study  (angiology,  neurology,  psychiatry,  gastro- 
enterology, dermatology,  lar3^ngology,  ophthalmology,  orthopedics, 
gynecology,  etc.).  Diagnosis  by  cooperative  groups,  with  an  integrator 
who,  after  collection  of  data  and  consultations  with  collaborators,  syn- 
thesizes the  total  findings  of  the  group  and  composes  the  clinical  picture 
with  balanced  ordination  of  its  parts,  is  the  highest  expression  by  the 
diagnostic  art  of  to-day  of  the  unity  obtainable  despite  this  differentia- 
tion, and  of  the  profit  derivable  from  specialization. 

The  Pure  Science  of  Clinical  Diagnosis 

Though  the  pure  science,  the  applied  science,  and  the  art  of  diagnosis 
are  most  often  treated  together,  it  is  helpful,  for  purposes  of  analysis, 
to  make  the  division  and  to  understand  how  the  three  differ  one  from 
another. 

By  the  pure  science  of  diagnosis,  we  mean  the  part  of  the  subject 
that  deals  with  the  general  laws  and  principles  of  diagnosis,  that  is. 


THE  APPLIED  SCIENCE  OF  DIAGNOSIS  637 

with  the  laws  and  principles  that  govern  the  recognition  of  health  and  of 
disease.  The  laws  of  diagnosis  are  generalizations  that  epitomize  in 
brief  formulae  uniformities  of  coexistence  and  of  sequence  among  the 
phenomena  of  health  and  of  disease.  The  causes  of  these  uniformities 
are  natural  forces  operating  under  like  conditions.  The  forces  con- 
cerned are  physical,  chemical,  biotic,  psychic,  and  social,  and  the  pure 
science  of  diagnosis  is  gradually  moving  toward  the  recognition  of  the 
workings  of  these  forces  as  manifested  in  the  phenomena  of  health  and 
of  disease.  In  the  construction  of  this  pure  science  of  diagnosis,  the 
data  are  derived  from  all  the  sciences  already  referred  to  as  fundamental 
for  diagnosis,  as  well  as  from  all  the  special  diagnostic  sciences.  The 
storehouse  of  knowledge  and  of  truths  discovered  in  the  science  of 
diagnosis  is  already  a  very  large  one.  Facts  have  been  classified  and 
are  ever  being  more  successfully  reclassified  as  the  laws  underlying 
them  and  the  causes  of  the  uniformities  are  being  ever  better  recog- 
nized. Subjective  symptoms  and  physical  signs  are  grouped  together 
as  S3'mptom-complexes  (or  syndromes),  and  these  are  uniformities  of 
coexistence  and  of  sequence  that  betoken  underlying  causes  acting  under 
like  conditions;  and  these  causes  and  these  conditions  are  slowly  being 
determined  by  the  host  of  investigators  who  are  ever  eagerly  striving 
to  discover  them.  Through  observation,  experimentation,  and  reflective 
thinking,  knowledge  concerning  the  symptoms  of  disease,  disease-com- 
plexes, the  sites  of  disease,  the  structural  and  functional  alterations  in 
disease  and  their  genesis,  the  forces  concerned,  and  the  conditions 
under  which  they  act,  is  being  organized  as  a  science  of  diagnosis  with 
some  well-established  principles.  The  diagnosis  of  disease  now  includes 
(i)  a  recognition  of  disturbed  function  in  disease  (pathological-physi- 
ological diagnosis),  (2)  a  recognition  of  the  site  and  nature  of  the 
structural  changes  in  disease  (pathological-anatomical  diagnosis),  (3)  a 
recognition  of  the  causes  of  disease  (etiological  diagnosis),  and  (4)  a 
recognition  of  the  relation  of  causes  to  the  sequence  of  conditions  in 
the  disease  (pathogenetic  diagnosis).  The  data  accumulated  by  workers 
in  all  the  medical  sciences  are  gradually  being  summarized,  arranged,  and 
classified  by  workers  in  the  science  of  diagnosis,  so  that  the  laws  and 
principles  underlying  them  are  slowly  becoming  evident. 

The  Applied  Science  of  Diagnosis 

Pure  science,  applied  science,  and  art,  progress  contemporaneously. 
Each  plays  into  the  hands  of  the  other  two;  there  are  ever  reciprocal 
contributions  to  healthy  growth. 

The  applied  science  of  diagnosis  has  the  task  of  finding  out  how 
the  laws  and  principles  of  the  pure  science  of  diagnosis  can  best  be 


638  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

applied  in  the  practical  work  of  recognizing  health  or  disease  in  persons 
who  present  themselves  for  examination.  This  applied  science  of  diag- 
nosis perceives  the  utilities  of  the  truths  of  "  pure "  science  and  sets 
about  devising  the  means  of  adjustment  that  are  necessary  to  actualize 
them.  It  invents  methods,  tools,  contrivances,  and  systems  of  pro- 
cedure, in  other  words,  the  "  machinery  of  diagnosis."  It  calls  to  the 
service  of  diagnosis,  from  the  other  sciences,  any  fact,  truth,  principle, 
or  invention  that  it  can  make  use  of,  directly  or  indirectly,  as  an  aid. 
It  becomes  familiar  with  the  methods  and  instruments  of  mathe- 
matics, chemistry,  biology,  psychology,  physics,  anatomy,  physiology, 
pathology,  bacteriology  and  immunology,  modifying  them  where  neces- 
sary to  meet  its  own  needs.  It  extends  the  simpler  methods  of  observa- 
tion of  patients  by  utilizing  instruments  of  precision  or  special  methods 
that  enormously  multiply  and  refine  the  possibilities  of  sense-impressions. 
Thus  the  sense  of  sight  is  extended  by  photography,  and  by  the  use  of 
the  microscope,  the  spectroscope,  the  ophthalmoscope,  the  bronchoscope, 
the  cystoscope,  the  roentgenoscope  and  a  hundred  other  devices.  The 
senses  of  smell  and  of  taste  are  chemical  senses  that,  unaided,  carry  us 
only  a  short  way  in  collecting  chemical  data  as  compared  with  the 
fact-accumulation  regarding  chemical  conditions  in  the  blood,  secre- 
tions, excretions  and  effusions  made  possible  by  the  clinical  chemists' 
adaptations  of  methods  devised  by  workers  in  physiological  and  patho- 
logical chemistry.  The  sense  of  hearing  is  extended  by  the  stethoscope, 
the  microphone  and  the  phono-cardiograph.  The  temperature-sense  is 
supplemented  by  the  clinical  thermometer.  The  sense  of  touch  and 
pressure  is  subtly  refined,  or  replaced,  by  various  ingenious  devices  such 
as  the  sphygmograph,  the  tonometer,  the  balance,  the  dynamometer  and 
the  string  galvanometer.  The  time-honored  methods  of  inspection, 
palpation,  percussion,  auscultation  and  mensuration  have  gradually  be- 
come expanded  into  an  observational  and  experimental  technique  that  is 
subtle  and  complex,  but  which  makes  for  ever  greater  objectivity  and 
precision.  Thus  by  devising  practical  technical  methods  that  can  be 
easily  made  use  of  in  examining  patients,  the  applied  science  of  diag- 
nosis is  ever  better  able  to  turn  to  account  the  truths  and  principles  that 
students  of  the  pure  science  of  diagnosis  have  established. 

Workers  in  the  applied  science  of  diagnosis  are  also  making  m.any 
efforts  better  to  organize  the  mode  of  conducting  clinical  examinations 
and  more  logically  to  arrange  the  several  steps  that  necessarily  must 
be  taken  to  arrive  at  satisfactory  diagnostic  conclusions.  That  the 
procedure  of  collecting  the  data  upon  which  a  diagnosis  is  based  and  of 
making  clinical  records  of  the  course  of  disease-processes  has  been 
systematized  in  the  interests  of  thoroughness,  completeness  and  accu- 


THE  ART  OF  CLINICAL  DIAGNOSIS  639 

racy,  can  easily  be  seen  l)y  comparing  the  contents  of  the  chnical  his- 
tories kept  to-day  (anamnesis,  status  praesens,  catamnesis,  epicrisis) 
with  those  that  have  come  down  to  us  from  the  diagnosticians  of  earher 
generations.  Moreover,  the  methods  of  applying  reflective  thought  to 
the  consideration  of  the  phenomena  observed  for  the  purpose  of  recog- 
nizing syndromes,  lesions,  causes  and  prospects  are  being  brought  into 
accord  with  the  general  method  of  science  and  with  the  newer  logic. 
The  purpose  of  a  diagnostic  study  decides  what  methods  shall  be  applied 
and  how.  In  every  case  there  must  first  be  a  recognition  of  the  existence 
of  a  diagnostic  problem;  observations  and  experiments  are  then  made 
to  locate,  and  more  accurately  to  define,  that  problem;  the  phenomena 
observed  are  arranged  and  brooded  over  until  suggestions  of  possible 
explanation,  or  recognition  of  meaning,  occur  to  the  mind;  the  implica- 
tions of  each  interpretative  suggestion  are  reasoned  out;  a  comparison 
is  made  between  each  suggestion,  with  all  its  implications,  and  the  facts, 
as  already  collected,  or  as  extended  by  further  observation  and  experi- 
ment; and  finally,  a  decision  is  reached  that  there  is  sufficient  reason  for 
the  acceptance  of  one  or  another  of  the  diagnostic  inferences  through 
corroboration,  and  for  the  rejection  of  other  suggestions  that  are 
proved  invalid  through  failure  of  corroboration.  If  no  suggestion  that 
has  been  entertained  can  be  found  to  be  valid,  no  diagnosis  is  made; 
the  mind  is  still  kept  open  and  judgment  is  kept  suspended  until  the 
process  has  been  gone  through  with  again.  An  attempt  to  accumulate 
more  facts  has  then  to  be  made,  the  occurrence  of  further  diagnostic 
suggestions  is  thus  favored,  and  these  in  turn  are  reasoned  out  as  to 
their  bearings  and  tested  for  their  validity.  In  this  way  the  best  diag- 
noses of  which  the  examiner  is  capable,  in  the  existing  state  of  his 
knowledge,  ability  and  opportunities,  are  reached.  The  representatives 
of  the  applied  science  of  diagnosis,  through  devising  new  and  better 
methods  of  examination,  through  arranging  for  their  more  orderly  em- 
ployment, and  through  conforming  to  the  usages  of  a  sound  logic,  occupy 
therefore  an  important  position  mediating  between  that  of  the  pure 
science  of  diagnosis  and  that  of  the  diagnostic  art. 

The  Art  of  Clinical  Diagnosis 

By  the  exercise  of  the  art  of  diagnosis  is  meant  the  skillful  carrying 
out  of  the  plans  and  methods  of  the  applied  science  of  diagnosis  (based 
upon  the  laws  and  principles  of  the  pure  science)  in  solving  actual 
problems  of  recognizing  health  and  disease  in  persons  who  present 
themselves  for  examination. 

Expertness  in  performance  and  capacity  to  make  and  deliver  a 
valuable  product  characterize  the  diagnostic  artist,  whether  he  is  active 


640         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

in  special  domains  only  or  whether  he  attempts  to  make  a  more  general 
diagnostic  survey.  Many  physicians  have  acquired  an  extensive  knowl- 
edge of  the  classifications  of  disease,  of  pathological  anatomy  and  physi- 
ology, and  of  etiology,  have  become  familiar  with  descriptions  of  the 
practical-technical  methods  in  use,  and  have  observed  skillful  prac- 
titioners of  the  art  of  diagnosis  at  work,  but  have  never  arrived  at  expert- 
ness  and  facility,  themselves,  in  the  actual  performance  of  diagnostic 
tasks.  There  are  other  physicians  who,  though  they  may  have  attained 
t6  real  skill  in  the  execution  of  certain  diagnostic  procedures,  have  never 
become  good  general  diagnosticians  owing  to  lack  of  a  comprehensive 
grasp  of  the  fundamental  laws  and  principles  of  diagnosis  or  owing  to 
insufficient  acquaintance  with  the  practical-technical  methods  of  diag- 
nostic work  other  than  a  few  in  which  they  have  acquired  accuracy  and 
facility.  Mere  exactness  in  outlining  an  area  of  dulness  by  percussion, 
mere  faultless  objectivity  in  description  of  the  sounds  audible  over  the 
heart  and  lungs,  or  mere  precision  in  the  conduct  of  a  roentgenoscopic 
examination  of  the  cardiovascular  stripe,  in  the  recording  of  a  sphygmo- 
gram,  or  in  the  quantitative  estimation  of  blood  sugar,  valuable  though 
any  or  all  of  these  procedures  may  be  in  collecting  data  to  be  used  in 
the  reasoning  process  that  precedes  the  arrival  at  a  legitimate  diagnostic 
conclusion,  can  be  exhibited  by  men  who  dare  lay  no  claim  to  mastery 
of  the  general  art  of  diagnosis.  As  a  matter  of  fact,  a  laboratory 
Diener  may  learn  to  carry  out  the  technique  of  the  Wassermann  reaction, 
or  of  the  differential  count  of  the  white  corpuscles  of  the  blood,  just 
as  accurately,  and  perhaps  more  speedily,  than  the  physician  who  employs 
him  and  who  has  instructed  him,  but  no  one  would  think  of  regarding 
such  a  laboratory  helper  as  proficient  in  the  general  art  of  medical 
diagnosis.  Owing  to  the  lower  dignity  of  his  employment,  he  must  be 
regarded  as  an  artisan  rather  than  as  an  artist.  An  adept  in  an  art 
of  medical  diagnosis  that  is  not  merely  local  or  special  in  its  aims  must 
have  acquired  at  least  some  skill  in  the  collection  of  data  in  all  the 
domains  pertinent  to  general  medical  diagnosis  and  must  possess  that 
wide  understanding  of  the  truths  and  principles  of  diagnostic  science 
and  that  ability  in  applying  them  that  will  permit  him,  on  reflective 
thinking  about  the  phenomena  observed  by  himself  or  by  those  who 
are  associated  with  him,  to  arrive  at  a  diagnostic  conclusion  or  belief 
that  is  warranted.  Ability  to  do  diagnostic  work  quickly,  accurately, 
and  effectively  and  capacity  to  produce  diagnostic  results  that  are 
adequate  to  the  purpose  in  view  are,  then,  the  marks  of  an  operator 
who  is  skilled  in  the  art  of  diagnosis. 

The  attainment  of  real  skill  in  the  general  diagnostic  art  is  no  easy 
matter.    It  presupposes  in  addition  to  good  natural  endowment,  a  thor- 


THE  ART  OF  CLINICAL  DIAGNOSIS  641 

ough  general,  and  special  education  for  the  developing  artist.  At  the 
basis  of  our  present-day  conception  of  the  training  of  medical  students 
lies  the  recognition  of  (i)  the  desirability  of  a  collegiate  education  pre- 
liminary to  the  study  of  medicine,  (2)  the  need  of  a  thorough  instruc- 
tion in  the  preclinical  sciences  and  in  the  organized  body  of  knowledge 
that  we  call  the  pure  science  of  medical  diagnosis,  and  (3)  of  the 
importance  of  a  closely-supervised  systematic  education  in  the  practical- 
technical  methods  of  accumulating  facts  pertinent  to  diagnosis  and 
in  the  logical  way  of  making  use  of  these  facts  (by  grouping  them,  by 
drawing  inferences  from  them,  by  testing  these  inferences  carefully  for 
their  validity  and  by  finally  reaching  legitimate  diagnostic  conclusions). 
The  requirements  for  admission  to  the  better  medical  schools  of 
our  time  are  such  that  the  students  entering  the  schools  have  had 
ample  opportunities  for  becoming  habituated  to  the  method  of  science 
and  for  acquiring  a  good  general  knowledge  of  nature  and  of  man 
as  an  individual  and  as  a  member  of  social  groups.  The  students  have 
all  had  instruction  in  mathematics,  physics,  chemistry  and  biology,  and 
many  of  them  have  studied  also  psychology,  logic  and  sociology.  In 
addition  to  a  training  in  the  use  of  their  native  language,  they  have 
acquired  a  reading  knowledge  of  one  or  more  modern  foreign  languages, 
have  learned  the  technique  of  using  libraries,  and  have  discovered  the 
value  of  consulting  sources  through  bibliographies.  The  prospective 
medical  students  with  such  a  preliminary  training  can  scarcely  have 
avoided  becoming  acquainted  with  the  general  methods  and  tools  of 
scientific  inquiry.  They  have  learned  how  problems  are  set  and  solved. 
They  have  been  taught  the  necessity  of  taking  pains  in  collecting  facts 
by  the  accurate  and  detailed  observation  of  phenomena  and  have  come 
to  appreciate  the  special  value  of  experimentation  in  which  observations 
are  made  under  rigidly  controlled  conditions.  Under  the  guidance  of 
good  teachers  they  have  begun  to  acquire  the  habit  of  reflective  thinking 
in  dealing  with  their  perplexities.  They  have  become  unwilling  to  jump 
to  conclusions  and  have  learned  to  insist,  when  confronted  with  a  dif- 
ficulty, on  temporarily  suspending  judgment  and  on  collecting  informa- 
tion that  will  more  rigidly  define  and  locate  that  difficulty;  and  when 
suggestions  of  possible  solution  of  a  problem  have  occurred  to  them 
on  brooding  over  their  facts,  they  have  been  taught  to  reason  out  the 
bearings  of  these  suggestions,  to  compare  them  and  their  full  implica- 
tions with  the  actual  facts  before  them,  and  thus  to  test  the  tentative 
ideas  of  solution  for  their  validity;  they  have  learned  the  importance, 
when  necessary,  of  making  more  observations  and  experiments  that 
will  either  corroborate  or  refute.  In  other  words,  they  have  had  the 
opportunity  to  practice  deliberative  thinking  before  undertaking  their 


642         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

medical  studies  proper.  On  entering  the  medical  school  they  spend  a 
couple  of  years  in  work  in  the  simpler  preclinical  medical  sciences  before 
engaging  in  the  much  more  complex  work  of  the  clinical  sciences  of 
diagnosis  and  therapy.  In  the  laboratories  of  anatomy,  of  physiology,  of 
physiological  chemistry,  of  pharmacology,  of  pathology  and  of  bacteri- 
ology they  continue  their  training  in  the  applications  of  the  method  of 
science  to  the  study  of  the  phenomena  dealt  with  by  these  special 
sciences,  and  they  should  come  out  of  these  laboratories  with  that  back- 
ground of  knowledge  and  that  familiarity  with  methods  that  is  indis- 
pensable for  any  proper  study  of  the  science,  and  any  skillful  practice 
of  the  art,  of  medical  diagnosis.  In  the  clinical  departments  of  the 
medical  school  the  students  then  enter  courses  of  instruction  in  the 
laws  and  principles  of  diagnosis  and  therapy,  begin  their  education  in 
the  technical  methods  of  these  sciences  and,  under  the  closest  supervision, 
make  a  start  in  the  practice  of  the  corresponding  arts.  Not  only  must 
the  methods  be  learned  (the  applied  sciences  of  diagnosis  and  therapy), 
but  skill  in  carrying  them  out  (the  arts  of 'diagnosis  and  therapy)  must 
be  acquired,  in  order  that  the  students  may  acquire  confidence  in  the 
reports  that  their  sense-organs  (thus  refined)  yield  and  in  the  warranty 
for  the  diagnostic  conclusions  that  can  be  reached  and  the  therapeutic 
regimens  that  can  legitimately  be  outlined  by  the  application  of  reflective 
thought  to  these  reports.  This  training  in  the  clinical  departments  in- 
cludes instruction  in  history-taking,  in  general  physical  diagnosis,  in 
clinical  laboratory  work,  in  X-ray  work,  and  in  the  technique  of  a  whole 
series  of  special  and  instrumental  methods  of  examination.  The 
students  learn  the  clinical  application  of  bacteriological  and  immuno- 
logical methods  to  be  used  in  the  diagnosis  of  the  infectious  diseases; 
they  are  taught  how  to  examine  the  respiratory  apparatus,  the  circulatory 
apparatus,  the  blood,  the  digestive  system,  the  urogenital  system,  the 
locomotor  system,  and  the  nervous  system  and  its  functions;  and  they 
also  receive  instruction  in  the  methods  of  clinically  investigating  the 
processes  of  metabolism  and  the  functions  of  the  endocrine  apparatus. 
After  this  more  or  less  thorough  drill  in  the  use  of  the  methods  of 
collecting  facts  regarding  each  special  domain,  they  begin,  as  clinical 
clerks  working  in  hospital  wards  and  dispensaries,  to  take  up  the  com- 
plete diagnostic  study  of  single  unknown  cases.  In  close  association 
with,  and  under  the  strict  control  of,  experienced  diagnosticians,  they 
record  anamneses,  make  physical  and  psychical  examinations,  resort  to 
laboratory  tests  and  X-ray  tests,  are  present  at  and  observe  closely  the 
examinations  made  by  experts  in  special  domains,  summarize  and 
rearrange  the  total  findings,  entertain  tentative  ideas  of  diagnosis  based 
upon  these,  consider  all  the  implications  of  such  suggestions,  and  try  to 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        643 

arrive  finally  at  diagnostic  ideas  that  can  be  corroborated.  Though  the 
students  are  encouraged  to  work  independently  as  far  as  possible,  they 
have  also  the  great  advantage  that  the  facts  they  collect  and  their 
reasoning  about  the  facts  are  subjected  to  frequent  review  and  criticism 
by  the  resident  hospital  assistants  and  by  the  older  and  more  experi- 
enced visiting  physicians.  Only  after  this  long  training  in  college, 
medical  school,  and  hospital  is  the  student  fitted  to  undertake  the  per- 
fecting of  his  skill  in  the  art  of  diagnosis,  and  long  experience  in  practice 
may  still  be  required  to  make  him  truly  expert. 

The  Actual  Process  of  Clinical  Diagnosis 

If  diagnostic  results  commensurate  with  the  medical  knowledge  of 
the  time  are  to  be  reached  when  an  internist  is  asked  by  a  patient  to 
make  a  diagnostic  study,  the  procedure  that  he  must  adopt  will  be  some- 
what prolonged  and  complex  and  may  be  divided  into  several  different 
stages:  (i)  the  recognition  of  a  problem  to  be  solved,  and  the  feeling 
of  a  diagnostic  difficulty;  (2)  the  accumulation  of  data  that  help  to 
locate,  and  to  define  the  diagnostic  problem;  (3)  the  consideration  of 
the  data  (accumulated,  summarized,  and  arranged)  that  suggestions  of 
possible  solution  of  the  diagnostic  problem  may  occur  to  the  mind; 
(4)  the  elaboration  by  reasoning  of  the  detailed  bearings  of  the  several 
suggestions  of  solution;  and  (5)  the  careful  testing  of  the  suggestions 
thus  minutely  worked  out  as  to  their  bearings  by  comparison  with  the 
facts  accumulated,  supplemented  when  necessary  by  other  facts  ob- 
tained by  further  observations  and  experiments,  this  careful  testing  lead- 
ing to  disbelief  in  the  unverifiable  suggestions  and  finally  to  belief  in 
the  suggestions  that  are  found  to  be  valid;  in  other  words,  the  arrival 
at  diagnostic  conclusions.  Each  of  these  five  stages  is  a  necessary  part 
of  any  diagnostic  study  that  aims  at  accuracy  and  completeness. 

The  course  pursued  by  a  worker  in  clinical  diagnosis,  then,  is  similar 
to  that  followed  by  everyone  who  engages  in  reflective  or  deliberative 
thinking  in  order  to  solve  his  problems.  Thus  the  same  five  stages 
must  be  passed  through  by  a  business  man  of  the  higher  type  when  he 
is  confronted  by  a  new  and  problematic  industrial  adventure.  The  same 
stopping-places  occur  in  the  path  of  an  engineer  who  is  given  the  task 
of  constructing  a  bridge.  And  the  same  points  are  recognizable  in  the 
line  along  which  any  scientific  investigator  moves  when  he  scents  a 
problem  that  interests  him,  goes  energetically  to  work  to  solve  it,  and 
finally  meets  with  success.  There  is  only  one  satisfactory  method  for 
solving  problems,  no  matter  what  the  domain,  and  that  method  is  the 
method  of  deliberative  thinking,  commonly  known  as  the  "  method  of 
science." 


644  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

Nowadays  a  modest  internist  makes  no  claim  to  powers  of  diagnosis 
von  Gottes  Gnaden;  instead,  he  recognizes  the  necessity  of  subjecting 
himself  gracefully  to  the  laws  of  logic  that  must  be  obeyed  not  only  by 
him  but  also  by  his  fellow- workers  in  the  higher  branches  of  human 
endeavor.  The  clinician  who  sees  and  hears  will  often  greatly  wonder; 
he  will  then  feed  himself  with  questionings  in  order  that  reason  may 
diminish  his  wonder.  He  will  observe  and  experiment;  he  will  brood 
over  and  speculate  upon  his  findings;  his  thick-coming  fancies  will  keep 
him  from  rest  until  he  has  tested  them  rigidly  as  to  their  validity  in 
all  their  implications;  he  may  even  distrust  his  eyes  and  will  wrangle 
with  his  reason  until  he  has  convinced  himself  that  the  evidence  in 
favor  of  one  set  of  conclusions,  and  of  one  only,  is  good  and  satisfying. 
He  will  observe  so  accurately,  he  will  experiment  so  appropriately,  he 
will  imagine  so  vividly,  and  he  will  verify  so  conscientiously  that  his 
diagnostic  conclusions  will  be  readily  defensible  and  will  be  concurred 
in  by  such  other  diagnosticians  as  are  keen  and  honest  observers,  skillful 
experimenters,  and  right  reasoners.  Feeling  a  difficulty,  observing  and 
experimenting  to  define  and  localize  it,  harboring  hypotheses  that  may 
solve  it,  reasoning  about  the  implications  of  these  hypotheses,  and  finally 
verifying  those  that  are  valid,  are  the  successive  steps  in  the  stairway 
of  the  process  of  diagnosis.  Clinical  diagnosis  is,  then,  an  arduous 
and  composite  process;  its  complexities  and  intricacies  are  imavoidable. 
But  practice  in  the  use  of  the  scientific  method  gives  strength,  speed, 
and  insight  to  him  who  employs  it.  Though  the  road  followed  by  the 
reflective  thinker  may  seem  long,  steep  and  involved,  it  is  the  only  safe 
way  to  as  much  of  certainty  in  diagnosis  as  the  knowledge  and  technique 
of  a  given  time  will  permit. 

Stage  I :  The  Recognition  of  a  Problem  to  he  Solved; 
Feeling  a  Diagnostic  Difficulty 

It  seems  worth  while  to  make  the  feeling  of  a  diagnostic  difficulty 
a  definite  stage  in  the  actual  process  of  clinical  diagnosis.  Formerly, 
more  often  than  now,  a  common  cause  of  incomplete  diagnostic  study 
was  a  lack  of  realization  of  the  difficulties  that  lie  in  the  way  of  accurate 
diagnosis.  This  was  true  especially  in  the  times  when  dogmas  prevailed 
among  physicians.  In  those  times  a  single  symptom,  say  the  complaint 
of  the  patient,  often  sufficed  for  the  making  of  a  diagnosis.  Thus  a 
headache,  a  cough,  a  palpitation,  or  a  pain  in  the  epigastrium,  gave  rise 
to  no  diagnostic  perplexity,  for  the  symptom  itself  was  regarded  as  a 
diagnosis  and  the  treatment  could  at  once  be  undertaken,  for  the  uni- 
versal principle  or  dogma  left  no  doubt  as  to  the  course  of  action  to  be 
pursued.     If,  nowadays,  a  patient  complain  of  a  headache,  we  at  least 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        645 

make  an  effort  to  discover  the  cause  of  the  headache  in  the  hope  that 
we  may  be  able  to  apply  a  rational  treatment;  we  are  not  content  with 
any  single  prescription  to  be  used  in  all  cases  of  headache.  Similarly, 
if  a  man  complain  of  a  backache,  the  scientific  practitioner  of  to-day 
will  not  resort  at  once  to  manipulative  or  other  therapy,  but  will  first 
undertake  a  thorough  investigation  of  the  case;  he  will  try  to  under- 
stand the  pathogenesis  of  the  condition  before  he  decides  upon  the  form 
of  treatment  to  be  applied.  Thus,  a  realization  of  the  difficulties  of 
diagnosis  protects  one  from  the  extreme  naivety  in  therapy  that  for- 
merly prevailed. 

Even  those  who  have  been  educated  in  the  best  medical  schools 
sometimes  fail  to  apprehend  clearly  the  extent  of  the  diagnostic  study 
that  is  necessary  in  certain  cases  to  insure  the  patient  that  he  shall  receive 
the  full  benefit  derivable  from  the  diagnostic  and  therapeutic  methods 
that  are  available.  A  practitioner  may  be  tempted  at  times  to  make  a 
"  snap-shot "  diagnosis  and  to  be  content  with  it,  but  if  he  yield  to  this 
temptation  often  and  curtail  his  diagnostic  studies  correspondingly,  he 
will  have  occasion  sooner  or  later  to  rue  some  of  his  hasty  conclusions. 
The  larger  the  experience  one  has  had  in  diagnosis  the  more  often  has 
he  demonstrated  that  clinical  conditions  that  at  first  seem  exceedingly 
simple  may  turn  out  to  be  very  complex.  In  many  cases  it  is  only  after 
numerous  data  have  been  collected  that  the  real  nature  of  the  physician's 
problem  becomes  apparent.  In  order,  then,  that  the  diagnostic  study  of 
a  given  patient  shall  be  sufficiently  comprehensive,  the  physician  must 
have  an  adequate  appreciation  of  the  diagnostic  difficulty  that  confronts 
him. 

One  of  the  principal  causes  of  detrimental  curtailment  of  diagnostic 
study  probably  lies  in  feeble  curiosity.  The  instinct  of  curiosity  is,  of 
course,  a  part  of  our  common  endowment.  When  we  see,  or  hear, 
something  that  we  do  not  fully  understand,  this  instinct  should  come 
into  function.  We  should  have  a  feeling  of  wonder  and  we  should  be 
driven  by  an  impulse  to  approach  and  examine  carefully  the  object  that 
excites  our  wonder.  Different  persons  are  doubtless  endowed  in  variable 
degree  with  this  inborn  impulse  closely  to  examine  objects  that  excite 
their  wonder.  The  impulse  grows  stronger  through  exercise,  weaker 
through  neglect.  It  Is  probable  that  many  persons  endowed  with  an 
instinct  of  curiosity  of  normal  strength  fail  to  profit  by  it  as  they 
should  owing  to  faulty  education.  A  normal  child  exhibits  regularly 
the  workings  of  the  instinct,  and  the  medical  student  and  the  physician 
should,  to  a  certain  extent,  try  to  remain  childlike  In  this  respect.  In 
clinical  diagnosis,  especially,  the  mind  should  be  kept  ever  on  the  alert, 
ever  sensitive  to  anything  out  of  the  ordinary,  ever  eager  for  new  experi- 


646         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

ence.  The  diagnostician  should  be  always  exploring,  continually  seek- 
ing new  materials  for  thought.  If  he  cultivate  a  healthy  curiosity,  if 
he  foster  the  emotion  of  wonder,  and  if  he  keep  strong  the  will  to 
investigate  in  order  that  wonder  may  diminish,  he  will  have  provided 
the  fundamental  conditions  that  protect  from  one-sided  and  incomplete 
diagnostic  studies  and  that  insure  the  comprehensive  survey,  the  accurate 
observation,  the  suitable  experimentation,  and  the  careful  reasoning  that 
lead  to  valid  diagnostic  conclusions. 

Stage  II:  The  Accumulation  of  Data  That  Help  to 
Localise  and  Define  the  Diagnostic  Problem 

Once  having  realized  that  we  are  confronted  by  a  diagnostic  difificulty, 
that  we  face  a  problematic  situation,  we  enter  upon  the  second  stage 
of  the  diagnostic  procedure  and  begin  to  accumulate  the  data  that  will 
permit  us  more  accurately  to  define  and  to  localize  the  diagnostic  problem. 
In  other  words,  we  avoid  any  immediate  attempt  at  solution  of  the 
problem  because  we  desire  first  to  get  a  better  idea  of  the  nature  of 
the  difficulty  before  us.  At  this  stage,  therefore,  restraint  of  inference 
and  suspension  of  judgment  are  desirable.  Even  though  suggestions  of 
solution  of  the  diagnostic  problem  arise  in  our  minds  as  we  proceed, 
it  is  best  not  to  yield  assent  to  them  at  this  stage,  even  when  they  seem 
plausible,  though  it  may  be  justifiable  to  pay  as  much  attention  to  them 
as  will  help  us  to  decide  upon  certain  directions  in  which  the  investigation 
may  be  intensively  undertaken,  or  to  conclude  that,  in  the  particular 
instance,  certain  tests  often  made  in  clinical  studies  may  safely  be 
omitted.  At  this  stage  we  must  be  sure  that  we  drag  our  net  over 
an  area  large  enough  to  insure  the  enclosure  of  enough  facts  regarding 
the  physical,  psychical  and  social  status  of  our  patient  to  make  the  diag- 
nostic problem  precise  in  localization  and  definition. 

The  accumulation  of  the  data  necessary  for  this  purpose  is  greatly 
facilitated  by  the  following  of  some  systematic  plan.  Thus  it  is  cus- 
tomary to  train  medical  students  to  collect  the  more  important  facts 
regarding  a  patient  in  a  certain  regular  way.  The  following  of  a  routine 
method  of  procedure  here  has  both  advantages  and  disadvantages. 
Among  the  advantages  are  ( i )  speed  in  the  performance  of  an  habitual 
process,  (2)  comprehensiveness,  and  (3)  convenience  of  arrangement 
after  the  facts  have  been  collected.  Among  the  disadvantages  may  be 
mentioned  (i)  the  danger  of  stifling  curiosity  by  too  rigid  adherence  to 
a  routine  program  and  (2)  the  danger  that  routine  may  not  be  varied 
from  time  to  time  as  knowledge  grows,  as  methods  become  elaborated, 
and  as  changes  of  emphasis  are  seen  to  be  important.     However,  the 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        647 

intelligent  and  experienced  diagnostician  should  know  not  only  when 
to  deviate  from  a  regular  routine  in  a  given  case,  but  also  how  to  modify 
his  routine  from  month  to  month  and  from  year  to  year  in  order  that 
his  practice  may  keep  pace  with  the  advances  of  his  science  and  his 
art.  The  beginner  in  diagnosis  does  well,  nevertheless,  to  adhere  rather 
closely  to  a  well-thought-out  scheme  for  the  collection  of  data  regarding 
patients;  after  he  has  attained  to  accuracy  and  celerity  in  applying  this 
routine  scheme,  he  may  begin  to  consider  the  occasions  when  he  is 
justified  in  modifying  it  or  in  diverging  from  it,  A  systematic  plan  of 
collecting  data  is  helpful  both  to  the  experienced  and  the  inexperienced 
diagnostician. 

We  may,  for  convenience,  deal  with  the  systematic  accumulation  of 
data  regarding  a  patient  in  five  different  parts : 

1.  The  recording  of  the  anamnesis. 

2.  The  recording  of  the  results  of  a  general  physical  and  psychical 
examination. 

3.  The  recording  of  the  results  of  the  application  of  laboratory 
tests. 

4.  The  recording  of  the  results  of  X-ray  examinations. 

5.  The  recording  of  the  results  of  more  intensive  examinations  of 
special  domains. 

ad  I. — The  Recording  of  the  Anamnesis.  In  collecting  the  data 
obtainable  as  answers  to  questions  put  to  the  patient  or  to  his 
friends  one  must  make  sure  that  the  questionnaire  covers  ( i )  the  main 
complaints  of  the  patient,  (2)  his  family  history,  (3)  his  personal 
history,  and  (4)  the  history  of  the  illness  for  which  he  consults  the 
practitioner,  including  the  symptoms  existing  at  the  time.  It  does 
not  matter,  as  a  rule,  in  what  order  these  several  parts  of  the  history 
are  taken.  Some  physicians,  after  ascertaining  the  main  complaint 
of  the  patient,  prefer  to  begin  with  the  family  history,  to  follow  this 
with  the  personal  history,  and  to  end  up  with  a  history  of  the  present 
illness.  Others  prefer  to  take  the  history  of  the  present  illness  first, 
and,  later,  to  secure  the  family  history  and  the  personal  history  of 
the  patient.  The  latter  method  has  some  advantages,  for  the  patient 
is  always  more  interested  in  talking  about  his  present  illness  than  in 
giving  the  details  of  the  h^'story  of  his  family  and  of  his  earlier  experi- 
ences. Thus  sick  people  often  exhibit  a  certain  impatience  if  one  begin 
with  the  family  history  rather  than  with  the  history  of  the  illness  itself, 
though  after  the  latter  has  been  given  in  detail,  they  will  willingly  re- 
spond to  inquiries  regarding  their  family  histories  and  their  earlier 
personal  histories.  In  the  accompanying  table  a  general  outline  is  given 
of  the  principal  points  to  be  covered  by  the  ordinary  anamnesis : 


648         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

A.  Main  complaints  of  the  patient, and  their  duration. 

B.  Family   history    (parents;   brothers,   and   sisters;   consort;   children;    other 

relatives). 

C.  Personal  history  (habits  of  work,  eating,  drinking,  smoking,  exercising,  rest- 

ing, sleeping,  relaxing,  etc.)  ;  education;  experience;  diseases;  operations; 
traumata ;  mental  conflicts ;  social  adaptations. 

D.  Present  illness  (onset;  supposed  causes;  course;  previous  treatment;  epitome 

of  symptoms  referable  to  different  anatomical-physiological  domains). 

It  is  important  when  recording  the  anamnesis  to  ask  questions  that 
bear  upon  the  presence  or  absence  of  certain  prominent  symptoms  refera- 
ble to  definite  domains  of  the  body;  such  inquiries  are  best  made  also 
in  systematic  sequence.  After  one  has  formed  the  habit  of  such  ques- 
tioning, a  catalogue  of  the  more  important  indications  can  be  easily  held 
in  the  mind.  But  the  beginner  will  do  well,  while  recording  the 
anamnesis,  to  have  before  him  a  list  of  these  symptoms,  to  make  sure 
that  he  overlook  no  inquiry  that  could  be  pertinent.  In  this  connection, 
the  following  list  of  betokening  symptoms  is  a  serviceable  one: 

Prominent  Symptoms. 

Pain   (topography;  time  relations;  severity;  quality;  radiations;  modifying 

influences;  associated  phenomena). 
Headaches. 
Dizziness. 
Tinnitus. 
Otorrhea. 
Nasal  catarrh. 
Sore  throat ;  hoarseness. 
Cough ;  sputum,  including  hemoptysis. 
Dyspnea. 

Palpitation;  irregular  action  of  heart. 

Retrosternal  or  precordial  oppression  or  pain  (relation  to  effort;  radiation). 
Swelling  of  ankles  or  face ;  varicose  veins. 
Ingesta    (quality;   quantity).     Disturbances   of  appetite  and   of   deglutition; 

trouble  with  teeth  and  gums. 
Nausea;  vomiting,  including  hematemesis. 
Gaseous  eructations ;  flatulence. 

Constipation ;  diarrhea ;  blood  or  mucus  in  stools ;  hemorrhoids ;  fistulae. 
Herniae. 

Pollakiuria;  dysuria ;  polyuria;  nocturia;  hematuria;  pyuria. 
Disturbance  of  sexual  functions  (male;  female). 
Symptoms  referable  to  muscles,  bones,  or  joints,  including  the  spine. 
Skin  eruptions ;  pigmentations ;  pruritus ;  loss  of  hair  or  nails. 
Disturbances  of  motility  (paralysis;  weakness;  wasting;  rigidity;  twitching; 

tremor;   spasms;   cramps;   fits;   ataxias;   dysarthria;   aphonia;   aphasia; 

apraxia). 
Disturbances  of  sensibility  (anesthesia ;  hyperesthesia ;  paresthesia,  especially 

tingling  in  the  fingers  and  toes;  defects  of  smell,  taste,  sight,  and  hearing). 
Mental  disturbances   (nervousness;  insomnia;  amnesia;  "fainting  spells"  or 

other  losses  of  consciousness;   delusions    [hypochondriacal,  melancholic, 

or  paranoid];  exaltation;  depression;  loss  of  interests;  fears;  indecision; 

inability  to  concentrate;  feelings  of  unreality;  social  maladjustments). 
Obesity ;  emaciation ;  changes  in  weight. 
Signs  of  infection  (fever;  chills;  sweats;  petechiae;  etc.). 

The  experience  and  common  sense  of  the  examiner  must  guide  him 
in  the  application  of  his  questionnaire  in  any  given  case.     There  may 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        649 

often  be  a  temptation  to  try  to  make  short  cuts  and  to  limit  the  ques- 
tionnaire unduly.  Such  abbreviation  should  be  permitted  only  most  cau- 
tiously, for  even  an  experienced  physician  may  easily  overlook  important 
clues  if  he  deviate  too  far  from  his  definite  systematic  plan  of  inquiry, 
or  if  he  reduce  too  much  the  number  of  inquiries  he  makes.  A  special 
warning  to  the  beginner  regarding  interrogations  concerning  sexual, 
psychical,  and  social  details  may  be  in  place.  It  is  often  difficult  to  judge 
how  far  one  ought  to  go  in  his  inquiry  at  the  first  interview  when  such 
details  seem  to  be  of  importance.  The  most  sagacious  and  adroit 
inquirer  will  here  sometimes  make  mistakes.  It  is,  therefore,  important 
for  a  beginner  to  go  slowly  and  cautiously  when  he  approaches  this  part 
of  the  anamnesis.  He  should  try  to  elicit  the  facts  in  an  easy,  conversa- 
tional way,  and  he  should  especially  avoid  giving  the  impression  that 
he  is  unnecessarily  curious  or  offensively  prying.  It  is  only  in  certain 
cases  that  the  details  of  the  sexual  life  must  be  inquired  into,  and  even 
then  the  mode  and  extent  of  the  inquiry  will  necessarily  be  influenced 
by  many  circumstances,  among  which  are  the  age,  intelligence,  char- 
acter, and  experience  of  the  patient.  In  determining  the  mental  status 
of  the  applicant,  too,  good  judgment  must  be  used  in  deciding  upon  the 
nature  and  extent  of  the  questions  to  be  asked.  One  never  asks  a  patient, 
for  example,  whether  he  has  delusions!  But  if  there  be  reason  to 
suspect  the  existence  of  pathological  ideas  in  the  patient's  mind,  his 
answers  to  the  four  questions  (i)  Are  you  sick?  (2)  Have  you  been 
sad,  blue,  gloomy,  depressed?  (3)  Do  you  blame  yourself  at  all,  or 
anyone  else,  for  your  trouble?  and  (4)  Has  everyone  treated  you  well? 
will  usually  reveal  the  presence  or  absence  of  hypochondriacal,  melan- 
cholic, and  paranoid  ideas  and  will  afford  sufficient  clues  for  the  further 
prosecution,  or  for  the  suspension,  of  investigation  in  these  directions. 
Psychoneurotic  patients  in  whom  it  is  often  desirable  to  hunt  carefully 
for  so-called  "  psychogenic  data  "  are  often  especially  sensitive  to  in- 
quiries regarding  their  personal  lives  and  their  adaptation  to  the  social 
environment.  If  on  cautious  approach  to  this  domain  the  patient  be 
found  unwilling  to  talk  at  the  first  interview,  it  may  be  wise  to  postpone 
this  part  of  the  inquiry  for  a  time.  A  little  later,  after  the  confidence 
of  the  patient  has  been  established  by  the  thorough  physical  examination 
made  and  by  the  sympathetic  attitude  of  the  physician,  it  will  be  more 
easily  possible  to  secure,  should  it  be  deemed  important,  the  full  avowal 
of  the  patient  regarding  his  more  intimate  life.  The  reticence  of  pa- 
tients regarding  abnormal  feelings  and  emotions,  moods,  ideas,  and 
experiences  is  easily  understandable,  and  even  though  questions  relating 
to  these  necessarily  form  a  part  of  the  daily  work  of  the  medical  prac- 
titioner, it  can  scarcely  be  expected  that  all  the  patients  will  willingly, 


650  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

and  immediately,  place  their  hearts  upon  their  sleeves  for  his  inspection. 
The  larger  the  world-experience  of  the  physician,  the  greater  his 
acquaintance  with  abnormal,  nervous,  and  mental  states,  the  wider  his 
sympathies,  and  the  more  winsome  his  personality,  the  easier  it  will 
be  for  him  quickly  to  acquire  the  confidence  of  patients  and  an  avowal 
of  the  sort  referred  to  when  it  is  desired  for  the  purposes  of  diagnosis. 
When  the  account  given  by  the  patient  suggests  the  existence  of  abnor- 
malities of  the  intellect,  of  the  emotions,  or  of  the  will,  it  may  be  helpful 
also  to  interview,  privately,  members  of  the  patient's  family  or  his 
business  associates,  in  order  to  learn  what  impressions  they  may  have 
formed  of  the  patient's  nervous  and  mental  state  and  what  alterations, 
if  any,  in  his  personality  they  have  observed.  By  the  prudent  application 
of  measures  such  as  those  described,  the  psychical,  social,  and,  when 
necessary,  the  sexual  status,  of  the  patient  can  nearly  always  be  satis- 
factorily estimated  and  recorded. 

Besides  the  general  features  of  the  anamnesis  above  referred  to 
there  are  certain  special  points  that  are  worthy,  perhaps,  of  particular 
mention.  One  of  these  is  the  significance  that  sometimes  pertains  to 
recording  the  precise  time-relations  of  the  appearance  of  different  symp- 
toms. Thus  when  a  tumor  of  the  acoustic  nerve  developing  in  the 
cerebello-pontine  angle  is  present,  the  exact  chronology  of  the  appear- 
ance of  the  different  symptoms  may  be  very  helpful  for  the  diagnosis. 
And  in  other  diseases  (typhoid  fever,  malaria,  syphilis)  the  temporal 
relations  of  the  symptoms  may  be  informative.  A  second  special  point 
in  the  anamnesis  worthy  of  attention  is  the  interpretation  given  by  the 
patient  himself  of  his  illness  as  a  whole,  or  of  any  single  symptom.  It 
is  desirable  to  put  such  an  interpretation  down  no  matter  how  improbable 
or  how  erroneous  it  may  seem  to  the  examiner.  Every  practitioner 
must  have  been  impressed  by  the  remarkable  interpretation-delusions 
that  patients  sometimes  harbor.  But  when  the  patient's  explanation  of 
his  condition  is  obviously  delusional,  some  care  must  be  taken  to  avoid 
too  brusque  a  refusal  of  acceptance  of  his  pathological  interpretative 
ideas.  Only  after  confidence  has  been  gained  through  a  thorough  inves- 
tigation and  through  the  establishment  of  a  sympathetic  relationship 
dare  the  practitioner  hope  to  change  such  firmly  set  opinions.  Even 
then  the  bringing  of  conviction  to  the  patient  may  not  be  possible  except 
through  a  somewhat  prolonged  reeducative  process.  A  third  matter  that 
may  well  be  again  emphasized  in  the  recording  of  the  anamnesis  is  the 
extension  of  the  questionnaire  so  that  it  shall  certainly  cover  the  marks 
of  disturbances  of  the  several  anatomical-physiological  systems  of  the 
body.  If  the  several  prominent  symptoms  mentioned  in  the  above  table 
be  inquired  about  and  the  answers  recorded,  it  is  not  likely  that  many 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS         651 

of  the  pathological  phenomena  self -observed  by  the  patient  will  be 
omitted  from  the  record  and  the  examiner  can  be  confident  that  he  has 
at  hand  the  data  necessary  for  his  guidance  in  the  further  progress  of 
the  diagnostic  investigation;  these  particulars  are  helpful  for  the  making 
of  decisions  regarding  the  necessity  of  more  intensive  explorations  in 
certain  domains.  Attention  to  the  exact  chronology  of  the  appearance 
of  symptoms,  the  appropriate  management  of  the  patient's  interpretative 
delusions  when  such  exist,  and  a  search  for  the  subjective  marks  of 
systemic  disturbances  are,  therefore,  especially  serviceable  to  the  phy- 
sician who  is  recording  a  patient's  recollections. 

The  totality  of  facts  that  the  anamnesis  can  yield  when  it  is  skillfully 
elicited  and  recorded,  has  an  importance  to  the  diagnostician  in  his 
appraisement  of  the  physical,  psychical,  and  social  status  of  the  patient 
under  study  that  can  scarcely  be  overestimated.  Both  the  anamnesis  and 
the  general  physical  and  psychical  examination  are,  of  course,  essential 
for  clinical  diagnosis,  and  neither  should  be  neglected.  I  have  heard 
more  than  one  good  clinician,  however,  state  that  if  they  had  to  be 
guided  by  one  or  the  other  alone,  they  would  prefer  to  follow  the  path 
shown  by  anamnestic  records  that  they  had  elicited  rather  than  by  the 
results  of  other  examinations.  These  were  men,  however,  who  through 
long  experience  had  learned  better  how  to  assess  the  value  of  single  sub- 
jective symptoms  and  groups  of  such  symptoms  than  any  beginner  could 
hope  to  do.  Fortunately,  we  do  not  have  to  be  guided  by  the  anamnesis 
alone  or  by  the  physical  examination  alone ;  we  utilize  both  to  supply  us 
with  the  symptoms  and  signs  that  clarify  for  us  the  diagnostic  problem 
by  which  we  are  confronted.  But  the  point  that  I  would  emphasize  here 
is  that  the  facts  obtained  by  recording  the  recollections  of  the  patient 
form  an  indispensable  part  of  the  data  we  accumulate  before  we  allow 
ourselves  to  consider  the  solution  of  any  problem  in  clinical  diagnosis. 

ad  2. — Recording  of  the  Results  of  a  General  Physical  and 
Psychical  Examination.  On  making  the  general  physical  and  psychical 
examination  it  is  desirable  to  dictate  the  findings  to  a  stenographer,  or 
to  a  stenotypist,  familiar  with  medical  terms,  item  by  item  as  the  exami- 
nation proceeds,  for  in  this  way  only  can  a  full  objective  record  be 
obtained.  It  is  not  safe  to  trust  the  results  of  such  an  examination 
even  in  so  far  as  to  attempt  writing  or  dictating  a  report  immediately 
after  the  examination  has  been  made.  The  examination  involves  so 
many  details  that  one  who  attempts  to  make  his  records  subsequently 
will  often  forget  points  of  importance.  Moreover,  the  record  made 
later  is  pretty  sure  to  be  colored  by  the  examiner's  total  impression 
derived  from  the  examination,  and  at  this  stage  of  the  diagnostic  study 
any   such   coloring   is   undesirable.    The   examiner   should    make    an 


652  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

unprejudiced  record  of  the  findings  in  each  region  quite  independent  of 
any  idea  of  what  the  ultimate  diagnostic  decisions  are  to  be. 

Before  undertaking  the  general  physical  examination  the  patient 
should  be  completely  undressed  and  placed  between  sheets  with  a  towel 
across  the  breasts,  and  the  lighting  arrangements  should  be  such  as  to 
permit  of  satisfactory  inspection.  How  many  errors  in  diagnosis  would 
be  avoided  if  practitioners  always  insisted  upon  the  undressing  of  the 
patient  before  the  examination  is  made!  Many  an  aortic  aneurysm, 
many  a  breast  tumor,  many  a  hernia,  many  a  bubo,  and  many  a  gibbus 
go  unrecognized  because  of  disobedience  to  this  fundamental  rule. 
Where  on  account  of  prudery  of  the  patient,  or  of  great  nervousness, 
or  of  other  cause,  a  complete  disrobing  is  not  practicable,  a  note  of  this 
should  be  made  in  the  record  in  order  to  call  attentioji  to  the  fact  that 
the  examination  has  been  made  under  hindering  conditions;  later  on, 
another  examination  can,  perhaps,  be  made  under  more  favorable  con- 
ditions, if  it  be  thought  desirable.  The  patient  should  be  under  observa- 
tion in  good  daylight,  the  source  of  the  light  preferably  being  on  the 
side  of  the  patient  opposite  to  that  of  the  examiner.  For  the  valuation  of 
pigmentations  of  the  skin  and  of  the  conjunctiva,  daylight  is  essential; 
for  the  rest  of  the  examination,  good  artificial  light  is  permissible  if 
daylight  be  unavailable.  Only  when  the  patient's  body  is  uncovered 
and  adequately  illuminated  can  one  expect  to  make  a  satisfactory 
physical  examination. 

When  recording  the  results  of  the  general  physical  and  psychical 
examination,  it  will  be  found  convenient  to  subdivide  the  record  into 
three  parts:  A.  General  points;  B.  Regional  examinations;  and  C.  Gen- 
eral examination  of  the  nervous  system  and  sense  organs.  Thus  the 
general  points  summarized  in  the  accompanying  table  should  first  be 
recorded : 

A.    General  Points. 

1.  Body  temperature;  pulse  at  both  wrists;  respiration. 

2.  Height ;  weight ;  calculated  ideal  weight ;  build  or  habitus ;  acra ;  nutri- 

tion; musculature. 

3.  Posture ;  gait ;  behavior, 

4.  Skin    (color;    thickness;   moisture;    eruptions;    ulcers;    pigmentation; 

scars;  striae;  nodules;  tumors;  superficial  blood  vessels;  edema). 

5.  Lymph  glands    (epitrochlear ;   superficial  and  deep  cervical;   occipital; 

posterior   auricular;    anterior   auricular;    submaxillary;    axillary; 
pectoral;  inguinal;  subinguinal;  popliteal). 

6.  Blood  pressure  (systolic;  diastolic). 

Passing  on  to  the  exploration  by  regions,  one  examines,  successively,  the 
upper  extremities,  the  head,  the  neck,  the  thorax,  the  abdomen  and 
pelvis,  and  the  lower  extremities.  There  is  a  special  reason  for  making 
the   examination   first   mainly   by   regions   rather   than   according   to 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        653 

anatomical-physiological  systems,  for  regional  examinations  better 
permit  one  to  accumulate  facts  without  too  much  regard,  at  the  moment, 
to  their  bearings  upon  the  conclusion  toward  which  the  whole  examina- 
tion is  aimed;  diagnostic  inferences  are  to  be  avoided  at  this  stage  of 
the  inquiry;  suspension  of  judgment  regarding  the  nature  of  the  pa- 
tient's ailment  is  at  this  time  desirable.  One  can  scarcely,  with  beginners 
in  diagnosis,  emphasize  too  strongly  this  restraint  of  inference  and  sus- 
pension of  judgment  while  the  facts  are  being  accumulated.  There  is 
a  great  tendency  among  those  who  have  never  learned  the  importance 
and  value  of  a  general  diagnostic  survey  to  seize  hold  of  some  salient 
feature  in  the  anamnesis  or  physical  examination,  to  allow  it  to  dominate 
all  of  the  further  investigations,  and  to  permit  it  detrimentally  to  curtail 
the  study  of  the  patient  as  a  whole.  Points  of  importance  to  be  noted 
in  the  regional  examinations  are  summarized  in  the  accompanying  table : 

B.  Regional  Examinations. 

1.  Head  (skull;  face;  eyes;  ears;  nose;  mouth;  throat;  glands). 

2.  Neck  (form;  thyroid;  tracheal  tug;  esophagus;  blood  vessels;  lymph 

glands;  cervical  spine;  cervical  ribs;  tumors;  wryneck), 

3.  Thorax   (form;  bones;  coverings;  breasts;  axillary  hirci  and  glands; 

lungs;  pleurae  and  mediastinum;  heart  and  aorta). 

4.  Abdomen  and  pelvis  (inspection,  percussion,  and  auscultation  of  abdo- 

men and  abdominal  viscera;  examination  of  rectum  and  of  uro- 
genital apparatus). 

5.  Extremities  (skin;  bones;  joints;  muscles;  nerves). 

After  having  made  a  record  of  the  general  points  and  of  the  points 
noted  under  regional  examinations,  it  is  well  even  at  this  stage  to  make 
at  least  a  general  examination  of  the  nervous  system  and  sense  organs, 
in  order  that  the  data  referable  to  the  nervous  system  accumulated 
during  the  regional  examination  may  be  supplemented  sufficiently  to 
prevent  us  from  overlooking  data  that  point  to  lesions,  or  to  disturbances 
of  function,  of  the  nervous  system.  Points  to  be  noted  in  this  pre- 
liminary examination  of  the  nervous  system  are  summarized  in  the 
following  table : 

C.  General  Examination  of  the  Nervous  System. 

1.  Sensory  functions  (cutaneous,  and  deep  sensibility;  stereognosis ;  spe- 

cial senses,  including  vision,  hearing,  smell,  and  taste). 

2.  Motor  functions  (muscular  power;  finer  movements,  including  speech 

and  writing;  coordination;  tonus). 

3.  Reflexes    (pupils;    deep    reflexes    of    extremities;    superficial    reflexes, 

plantar  and  abdominal;  sphincters). 

4.  Autonomic  functions  (vasomotor;  secretory;  trophic). 

5.  Mental   state*    (orientation;    memory;    calculation;    attention;    sense 

deceptions;  pathological  ideas;  mood;  psychogenic  data;  etc.). 

*  If  the  exploration  in  this  direction  has  been  full  enough  and  systematic  enough 
in  the  recording  of  the  anamnesis,  it  may  be  omitted  here. 

In  making  such  a  general  physical  and  psychical  examination  we 
call  upon  our  powers  of  clinical  observation  and  of  clinical  experimenta- 


654         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

tion  and  these  functions  should  be  exercised  in  an  orderly  and  balanced 
manner.  In  simple  observation  we  note  and  record  conditions  that 
we  do  not  alter.  In  an  experiment  we  exert  some  influence  upon  the 
character  of  the  event  that  we  observe,  that  is,  our  observations  are 
then  made  under  altered  conditions.  Every  clinical  examination  in- 
cludes these  two  modes  of  experience  long  ago  referred  to  by  Herschel, 
the  astronomer,  as  "passive  and  active  observation."  The  technique  of 
clinical  observation  and  experimentation  has  to  be  learned  slowly.  In 
our  better  medical  schools  the  students  are  drilled  in  one  method  after 
another  until  a  certain  amount  of  skill  is  acquired.  But  the  practitioner 
goes  on  increasing  his  skill  as  his  experience  grows.  The  well-trained 
and  experienced  practitioner  can  make  a  general  physical  and  psychical 
examination,  such  as  that  outlined  above,  very  quickly  and  accurately. 
But  even  the  well-trained  man  should  examine  himself  from  time  to  time 
for  tendencies  to  error.  One's  methods  of  examination  by  observation 
and  experiment  are  undoubtedly  easily  influenced  by  his  special  inter- 
ests. The  making  of  an  objective  record  of  facts  without  bias  is  not 
easy,  especially  if  they  come  into  conflict  with  one's  own  peculiar  views. 
It  is  surprising  how  some  men  will  always  find  tenderness  at  McBurney's 
point,  or  in  the  right  hypochondrium,  how  others  will  always  find  a  few 
crackles  in  one  interscapular  space,  how  others  will  nearly  always  find  a 
vertebral  spine  out  of  alignment,  how  others  will  suspect  the  existence 
of  a  stricture  of  the  ureter,  and  how  others  will  always  regard  a  pa- 
tient's feelings  and  behavior  as  psychoneurotic  in  type.  Men  are  very 
prone  to  find  what  they  are  looking  for  and  it  is  easy  to  decide  that 
very  slight  deviations  from  normal  are  worthy  of  being  regarded  as 
pathological  findings  if  they  be  in  the  line  of  one's  special  clinical  inter- 
ests. Minute  and  accurate  observations  are  of  course  desirable,  but 
one  must  remember  that  the  accurate  recording  of  very  minute  devia- 
tions in  one  domain  (the  domain  of  one's  special  interest)  if  accom- 
panied by  failure  of  observation  of  grosser  deviations  from  normal  in 
other  domains  may  result  in  an  unbalanced  study  and  in  fallacious 
diagnostic  inferences.  When  several  special  examiners  have  cooperated 
with  an  internist  in  the  clinical  study  of  a  patient  it  is  of  interest,  when 
going  over  all  the  findings,  to  see  how  often  the  special  interests  of 
the  several  collaborators  have  colored  the  record.  The  observations  and 
experiments  made  upon  a  patient  should  always  be  conducted  with 
proper  regard  to  a  sense  of  symmetry  and  proportion,  for  there  shoitld 
be,  in  the  clinical  record,  a  "  due  and  harmonious  admeasurement  of  the 
parts  to  each  other  and  to  the  whole." 

The  report  of  the  general  physical  and  psychical  examination,  after 
it  has  been  typewritten,  is  placed  along  with  the  record  of  the  anamnesis, 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        655 

pending  the  arrival  of  the  records  of  results  of  laboratory  examinations, 
of  X-ray  examinations,  and  of  examinations  in  special  domains.  It  is 
best  to  accumulate  all  this  material  before  attempting  to  summarize  the 
data  and  to  rearrange  them  according  to  the  anatomical-physiological 
systems  to  which  they  may  be  especially  related. 

ad  3. — Recording  of  the  Results  of  the  Application  of  Laboratory 
Tests.  The  methods  of  the  clinical  laboratory,  as  developed  in  recent 
years,  yield  data  of  real  importance  for  clinical  diagnosis.  When  making 
a  general  diagnostic  survey  of  a  patient,  suffering  from  some  obscure 
malady,  certain  routine  tests  are  now  commonly  made  in  hospitals  and 
in  the  ofiEices  of  consultants.  These  include  examinations  of  the  blood, 
of  the  sputum,  of  the  stomach  contents,  of  the  feces,  and  of  the  urine. 
Just  how  much  laboratory  work  shall  be  decided  upon  as  a  minimum 
routine  requirement  in  every  general  diagnostic  survey  will  vary  with 
different  clinicians.  There  is  a  general  tendency  at  present  to  have 
made  as  a  routine  in  every  case  that  is  at  all  obscure,  unless  for  some 
reason  one  or  more  of  them  is  contraindicated,  the  laboratory  tests  men- 
tioned in  the  following  table : 

A.    Routine  Laboratory  Tests. 

1.  Examination  of  blood. 

Red  blood  corpuscles ;  count,  with  notes  on  size  and  form. 

White  blood  corpuscles ;  count. 

Differential  count  of  white  blood  corpuscles  in  stained  smears. 

Platelets. 

Search  for  parasites. 

Wassermann  reaction. 

2.  Examination  of  sputum  (especially  for  (i)  tubercle  bacilli  and  other 

bacteria  and  parasites,  (2)  tissue  fragments,  (3)  spirals,  (4)  elastic 
fibers,  (5)  cells,  and  (6)  crystals). 

3.  Examination  of  stomach  contents. 

Free  HCl,  combined  HCl,  and  total  acidity. 
Occult  blood. 
Lactic  acid. 
Oppler-Boas  bacilli. 

4.  Examination  of  feces. 

Macroscopic  and  microscopic  appearances. 

Undigested  food  (meat;  fats;  starch). 

Occult  blood. 

Bile. 

Parasites,  or  their  eggs. 

5.  Examination  of  urine  (night  and  day  specimens). 

Physical  (color;  reaction;  specific  gravity). 
Chemical  (albumin;  sugar;  bile;  indican ;  diacetic  acid). 
Microscopical  (red  blood  corpuscles;  white  blood  corpuscles; 
casts). 

Some  clinicians  will  be  satisfied  with  a  less  comprehensive  routine 
requirement  and  there  are  others  who  will  desire  a  more  extensive  series 
of  laboratory  tests  in  every  case.  But  no  matter  what  routine  require- 
ment one  decides  upon,  it  is  often  desirable,  in  special  cases,  to  have 
certain  other  laboratory  tests  made.     Thus  when  there  are  signs  of 


656         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

infection  with  continuous  fever  of  unknown  origin  a  blood  culture  will 
be  made,  but  it  is  quite  unnecessary  to  make  a  blood  culture  as  a  routine 
examination  in  every  patient  who  presents  himself.  A  lumbar  puncture 
with  examination  of  the  cerebrospinal  fluid  may  seem  desirable  if  a 
patient  who  has  had  lues  years  before  presents  nervous  symptoms  sug- 
gestive of  involvement  of  the  cerebrospinal  nervous  system,  or  if  in  any 
patient  there  be  signs  of  meningeal  irritation,  or  if  one  suspect  the 
existence  of  an  epidemic  encephalitis  or  of  a  Heine-Medin  infection; 
but  it  would  be  an  unnecessary  procedure  to  examine  the  cerebrospinal 
fluid  as  a  routine  measure  in  every  patient  who  comes  for  examination. 
Again,  if  a  peculiar  arrhythmia  present  itself  in  the  course  of  the  regional 
examination,  it  may  seem  desirable  to  have  polygraphic  tracings  of  the 
radial  and  jugular  pulse  and  of  the  movements  of  the  heart's  apex,  or  an 
electrographic  study,  though  to  apply  the  polygraph  and  the  electro- 
cardiograph to  every  patient  in  practice  would  be  a  waste  of  time  and 
energy.  Laboratory  tests  in  great  variety  have  been  devised,  but  our 
clinical  laboratories  are  gradually  sifting  out  the  less  important  oneS; 
and  we  are  slowly  becoming  familiar  with  the  best  methods  for  securing 
the  different  kinds  of  valuable  information  that  the  clinical  laboratory 
can  yield.  Among  the  special  laboratory  tests  occasionally  required  may 
be  mentioned  the  following : 

B.    Special  Laboratory  Tests  (to  be  made  in  certain  cases). 

1.  Cerebrospinal  fluid  (lumbar  puncture). 

2.  Tuberculin  tests. 

3.  Excision  of  a  gland,  a  piece  of  muscle,  or  a  nodule,  or  making  uterine 

scrapings,   for  histological   examination. 

4.  Bacteriological    smears    and    cultures    (blood;    sputum;    urine;    pus; 

prostatic  milkings;  cerebrospinal  fluid,  etc.). 

5.  Blood  chemistry;  and  other  special  blood  examinations    (agglutinins; 

lysins;    opsonins;    coagulation-time;    bleeding-time;    content    in 
coagulation-factors;  etc.) 

6.  Renal  function  tests. 

7.  Metabolic  studies. 

8.  Protein  sensitization  tests. 

9.  Pharmacodynamic  tests  (w'ith  epinephrin,  pilocarpin,  or  atropin). 

10.  Electrocardiography. 

11.  Sphygmography. 

12.  Exploratory  punctures. 

13.  Animal  inoculations. 

Some  practitioners,  especially  young  men  recently  trained  in  the 
medical  schools,  make  all  of  the  laboratory  tests  required  themselves. 
Others  make  only  their  routine  laboratory  tests  and  depend  upon  special 
laboratory  workers  for  the  performance  of  the  special  tests.  Still 
others  have  all  their  laboratory  tests  made  for  them  by  assistants,  or 
by  special  clinical  laboratory  workers. 

Since  the  results  of  laboratory  tests  have  come  to  be  so  highly  valued 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        657 

in  diagnosis,  clinical  laboratories  have  been  so  greatly  multiplied  and  the 
number  of  persons  professing  to  do  expert  clinical  laboratory  work  has 
so  greatly  grown,  that  it  may  be  in  place  to  sound  a  note  of  caution. 
Unfortunately  the  sudden  demand  for  laboratory  tests  has  occasioned  a 
supply  of  laboratories  and  of  laboratory  workers  that  contribute  results 
of  variable  value.  Too  often  the  work  done  is  unsatisfactory.  Much 
harm  can  result  from  inaccurate  reports  emanating  from  unreliable 
laboratory  workers.  Even  the  v/ell-trained  worker  in  the  best  clinical 
laboratory  will  make  a  mistake  occasionally  in  the  performance  of  some 
test.  Especially  is  this  true  of  the  Wassermann  reaction.  Every  effort 
should  therefore  be  made  to  insure  the  avoidance  of  erroneous,  or 
inaccurate,  laboratory  reports.  The  value  of  a  general  diagnostic  survey 
is  not  infrequently  vitiated  by  an  unwarranted  credence  in  a  laboratory 
report. 

It  should  further  be  emphasized  that  when  practitioners  call  upon 
their  co-workers  in  the  clinical  laboratories  for  the  making  of  special 
tests,  they  should  not  expect  the  laboratory  men  to  make  their  diagnoses 
for  them.  They  should  ask  for,  and  expect,  only  reports  upon  the  par- 
ticular laboratory  tests  mentioned.  The  results  of  these  tests  should 
be  valued  in  association  with  the  results  obtained  by  other  methods  of 
examination.  It  is  only  occasionally  that  a  laboratory  can  report  a 
result  that  is  pathognomonic  for  diagnosis  (positive  Wassermann; 
positive  streptococcus  culture  or  typhoid  culture  from  the  blood; 
meningococcus,  or  tubercle  bacilli,  from  the  cerebrospinal  fluid,  etc.). 
One  must  remember,  too,  that  even  a  pathognomonic  finding  by  means 
of  a  laboratory  test,  though  it  reveal  the  existence  of  a  certain  disease 
in  a  patient,  may  not  point  to  the  pathological  condition  that  is  most 
important  when  the  patient's  whole  state  is  considered.  A  man  may 
have  syphilis  and  a  glioma  of  his  brain  at  the  same  time.  Another  man 
may  suffer  from  amebic  dysentery  and  from  leukemia  at  the  same  time. 
The  report  of  a  positive  Wassermann  reaction  in  the  blood  in  the  one 
instance,  and  the  demonstration  of  the  presence  of  amebae  in  the  stools 
in  the  other,  though  not  to  be  underestimated  in  value,  would  not  point 
to  the  pathological  conditions  of  paramount  importance  for  the  two 
patients  mentioned.  Our  diagnostic  study  in  any  given  case  should  be 
comprehensive  enough  to  include,  in  the  final  summing-up,  all  the  im- 
portant deviations  from  the  normal  presented  by  the  patient,  arranged 
in  the  order  of  their  relative  importance.  But  no  attempt  at  the  ultimate 
diagnosis  of  the  case  should  be  permitted  at  the  stage  of  examination 
now  under  description.  The  restraint  of  inference  and  the  suspension 
of  judgment  that  have  been  repeatedly  emphasized  should  be  continued 
until  all  of  the  data  of  our  schema  have  been  accumulated,  including 


658  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

those  already  referred  to  and  those  obtainable  by  X-ray  examinations 
and  by  intensive  examinations  in  special  domains. 

ad  4. — The  Recording  of  the  Results  of  X-ray  Examinations. 
The  X-ray  laboratory,  like  the  clinical  laboratory,  has,  in  recent  times, 
made  important  contributions  to  the  methods  of  clinical  diagnosis  and 
is,  accordingly,  now  much  appealed  to  for  help  in  accumulating  data 
regarding  patients  undergoing  diagnostic  study.  At  first  employed 
chiefly  in  surgical  diagnosis,  the  X-ray  laboratories  to-day  are  utilized 
even  more  by  internists  than  by  surgeons.  Many  practitioners  install 
a  roentgenological  department  in  their  own  office  and  do  X-ray  work 
themselves,  or  arrange  for  a  roentgenological  assistant.  Others  send 
their  patients  to  X-ray  laboratories  conducted  by  physicians  who  limit 
their  work  to  roentgenology.  The  great  improvements  that  have  been 
made  in  the  manufacture  of  roentgenological  apparatus  have  rendered 
the  technique  of  X-ray  examinations  much  more  simple  than  formerly, 
so  that  any  intelligent  person  can  be  trained  to  make  good  roentgeno- 
grams of  the  bones,  joints,  teeth,  lungs,  heart  and  aorta,  and  alimentary 
canal.  The  accurate  interpretation  of  the  roentgenogram  is,  however, 
not  such  an  easy  matter.  In  the  first  place,  no  one  but  a  medical  man 
trained  in  anatomy,  pathology,  and  the  clinics  can  be  expected  ade- 
quately to  interpret  what  can  be  seen  in  a  roentgenogram,  or  what  is 
visible  on  roentgenoscopic  examination.  Even  among  medical  men 
who  devote  their  whole  time  and  energy  to  roentgenological  work  the 
interpretative  powers  vary  greatly,  depending  partly  upon  native  endow- 
ment and  partly  upon  length  and  intensity  of  experience.  There  can 
be  no  doubt  that  roentgenoscopic  examinations  and  roentgenograms 
carefully  made  and  properly  interpreted  are  valuable  contributions  to 
the  data  with  which  the  modern  diagnostician  should  be  supplied  when 
he  is  studying  obscure  conditions. 

The  importance  of  close  cooperation  between  internists  and  roent- 
genologists is  growing  every  day  clearer.  An  internist  who  to-day  is 
unable,  himself,  to  interpret  roentgenoscopic  and  roentgenographic  find- 
ings is  decidedly  handicapped  in  his  diagnostic  work,  for  even  though 
he  receive  objective  reports  from  competent  roentgenological  experts 
it  will  be  hard  for  him  to  value  these  reports  in  a  proportionate  way. 
Any  clinician  who  has  made  an  extensive  study  of  X-ray  plates  and  who 
has  familiarized  himself  with  what  can  be  seen  on  a  fluoroscopic  screen 
will  testify  to  the  great  autodidactic  advantage  that  results  from  com- 
bining personal  roentgenological  interpretation  with  the  results  obtain- 
able by  other  clinical  methods.  Not  that  the  hard-working  internist 
can  expect  to  become  as  proficient  in  the  interpretation  of  plates  and 
screen  views  as  are  professional  roentgenologists  who  give  their  whole 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        659 

time  and  energy  to  roentgenological  work.  The  close  association  of 
the  expert  internist  with  the  expert  roentgenologist  is  essential  to  the 
highest  quality  of  work  of  each.  The  diagnostician  who  does  not  see 
the  X-ray  plates  on  his  own  patients  misses  a  great  deal  and  the  roent- 
genologist who  is  never  able  to  control  the  results  of  his  X-ray  examina- 
tions by  the  clinical  history  of  the  patient  or  by  the  physical  examination 
made  by  the  internist  will  fall  into  serious  errors  and  will  not  grow  as 
rapidly  in  X-ray  interpretation  as  he  should.  Regular  conferences 
should,  therefore,  be  arranged  between  internists  and  associated  roent- 
genologists. 

Altogether  too  much  reliance  is  placed  at  present  by  many  prac- 
titioners upon  the  reports  in  the  form  of  diagnoses  rather  than  in  the 
form  of  concrete  objective  descriptions  of  their  actual  findings  that  are 
made  by  some  roentgenologists.  The  latter  are  perhaps  not  so  much  to 
blame  for  this  as  are  the  practitioners  who  pressingly  solicit  them  to 
give  specific  diagnostic  judgments  based  upon  their  X-ray  plates.  It 
may  be  very  helpful,  of  course,  to  have  the  diagnostic  impression  of  the 
experienced  roentgenologist  in  addition  to  the  objective  description  of 
his  findings.  But  the  diagnostician  making  the  general  survey  of  the 
patient  should  be  on  his  guard  against  accepting  too  readily  the  diag- 
nostic impression  of  the  roentgenologist.  The  internist  should  pay 
much  more  attention  to  the  objective  description  of  the  findings  dis- 
covered by  X-ray  methods  than  to  such  diagnostic  impressions,  and 
should  utilize  these  objective  reports  in  connection  with  the  data  col- 
lected by  all  other  methods  in  arriving  at  his  diagnostic  conclusion; 
otherwise  he  will,  at  times,  be  led  astray  by  a  positive  diagnosis  ventured 
by  the  roentgenologist. 

General  diagnosticians  can,  in  turn,  be  very  helpful  to  roentgenolo- 
gists if  they  will  report  to  the  latter  (i)  the  ultimate  diagnostic  con- 
clusions to  which  they  arrive  after  the  study  has  been  completed,  and 
(2)  a  summary  of  the  data  upon  which  the  complete  diagnosis  is  based. 
We  must  gradually  work  out  the  methods  by  which  roentgenology  and 
internal  medicine  can  be  reciprocally  most  helpful.  If  the  internist  and 
the  roentgenologist  will  each  give  his  best  and  if  arrangements  can  be 
made  for  frequent  conferences  and  discussions  regarding  the  find- 
ings in  concrete  cases,  the  accuracy  of  diagnostic  studies  requiring 
the  cooperation  of  internists  and  roentgenologists  will  be  rapidly 
advanced. 

When  one  is  making  a  general  diagnostic  survey  of  an  obscure 
case  it  is  a  real  comfort  to  be  supplied  with  the  data  that  roentgen- 
ology can  yield  regarding  the  structures  mentioned  in  the  following 
table : 


66o         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

Commoner  Medical  X-ray  Examinations. 

1.  The  paranasal  sinuses. 

2.  Dead  teeth  and  unerupted  teeth. 

3.  The  contents  of  the  thorax  (form;  size;  opacity  or  transparency). 

4.  The  digestive  tract  as  revealed  in  X-rays  during  and  after  ingestion  of 

barium  (deglutition:  form,  size,  and  motility  of  stomach  and  of  dif- 
ferent parts  of  intestine). 

Roentgenograms  of  the  paranasal  sinuses  and  of  suspicious  teeth 
together  with  a  roentgenoscopic  report  on  the  thorax  and  abdomen  if 
made  in  the  practitioner's  own  office  can  be  done  at  very  small  expense, 
so  small  that  many  practitioners  could  include  the  charge  for  such 
reports,  when  made  as  a  routine  measure,  in  the  general  consultation 
fee.  Only  if  the  symptoms  or  physical  signs  point  definitely  to  marked 
disturbance  of  the  digestive  functions,  or  if  in  the  absence  of  such 
symptoms  and  signs  the  roentgenoscopic  examination  done  for  elimina- 
tive  purposes  reveal  suspicious  findings,  need  the  more  expensive  serial 
roentgenograms  of  the  gastrointestinal  tract  be  made.  The  data  ob- 
tainable by  the  simple  and  commoner  X-ray  examinations  enumerated 
in  the  above  table  go  far  toward  protecting  the  physician  who  is  making 
a  general  diagnostic  survey  of  a  patient  from  making  certain  sins  of 
omission  and  commission  that  are  frequent. 

In  addition  to  such  routine  roentgenological  examinations,  certain 
special  X-ray  examinations  may  be  indicated  by  the  records  of  the 
anamnesis,  by  the  results  of  the  general  physical  examination,  or  by 
the  preliminary  roentgenological  survey  of  the  thorax  and  abdomen.  A 
list  of  the  roentgenological  examinations  most  often  used  is  included 
in  the  following  table : 

Special  X-ray  Exaiiiiiiations  (to  be  made  zvheii  indicated). 

1.  Stereoscopic  roentgenogram  of  skull,  of  sella  turcica,  or  of  mastoid  por- 

tion of  temporal  bone. 

2.  Stereoscopic  roentgenograms  of  lungs  and  pleurae. 

3.  Teleroentgenogram  of  the  heart. 

4.  Serial  roentgenograms  of  the  gastrointestinal  tract. 

5.  Roentgenograms  of  the  gall-bladder  area. 

6.  Roentgenograms  of  bones,  joints,  and  spine. 

7.  Roentgenograms  for  renal,  ureteral,  and  vesical  calculi. 

8.  Pyelograms  and  ureterograms  after  thorium  injection. 

9.  Ventriculograms  after  trephining  and  injecting  air  into  the  cerebral  ven- 

tricles. 
10.    Bronchiograms    after   insufflation    of   a   bronchus   with   bismuth   subcar- 
bonate  through  the  bronchoscope. 

One  files  the  records  of  the  results  of  any  X-ray  examinations  made, 
along  with  the  other  reports,  pending  the  collection  of  data  derived  from 
the  intensive  examinations  of  special  domains  that  have  become  suspect 
from  a  consideration  of  the  anamnestic  and  physical  study. 

ad  5. — The  Recording  of  the  Results  of  Intensive  Examinations 
of   Special   Domains.     In    making  ,a   general    diagnostic    survey,    an 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        66i 

internist  must  ask  himself  what  systems  of  the  body  of  the  patient 
require  an  especially  intensive  study  and  how  the  intensive  study  shall 
be  conducted.  While  taking  the  anamnesis  and  dictating  notes  on  the 
physical  and  the  psychical  status  of  his  patient,  the  examiner  will  have 
had  his  attention  arrested  at  intervals  by  the  discovery  of  symptoms  or 
signs  that  his  experience  has  taught  him  are  most  frequently  referable 
to  disturbances  of  function  in  particular  anatomical-physiological  do- 
mains. Though  in  general  restraining  inference  and  suspending  judg- 
ment regarding  the  final  outcome  of  his  study  the  positively  abnormal 
findings  that  have  thus  arrested  his  attention  will  serve  as  clues  to  sug- 
gest certain  special  lines  of  inquiry;  they  guide  him  to  the  domains  that, 
in  the  particular  case,  merit  a  more  thorough  study  than  that  made  in 
the  course  of  a  general  routine  examination.  Thus  the  complaint  of 
oppression  in  the  chest  on  exertion  or  the  observation  of  an  increased 
blood  pressure,  of  an  arcus  senilis  or  of  a  cardiac  arrhythmia,  may  point 
to  the  desirability  of  an  especially  thorough  study  of  the  cardio-vascular 
system.  In  another  case,  a  history  of  recurring  epigastralgia,  of  gaseous 
eructations,  or  of  persistent  constipation  will  lead  the  examiner  to  under- 
take a  special  study  of  the  digestive  apparatus.  In  another,  the  historj^ 
of  frequent  micturition  during  the  night,  of  difficulty  in  starting  the  flow 
of  urine,  or  of  hematuria,  may  make  an  examination  of  the  urogenital 
system  by  special  methods  imperative.  Or  again,  the  presence  of  a 
polyarthritis  will  suggest  to  the  examiner  the  importance  of  studying 
intensively  all  those  domains  of  the  body  in  which  focal  infections  that 
may  give  rise  to  metastatic  infections  of  the  joints  occur.  In  such  cases 
the  question  arises.  How  shall  this  intensive  study  of  special  domains 
to  which  certain  symptoms  or  signs  point  be  undertaken?  How  can 
the  data  pertaining  to  these  particular  domains  be  most  accurately,  most 
quickly,  and  most  inexpensively  collected  ? 

During  the  past  fifty  years  the  technical  methods  of  diagnosis  and 
therapy  have  been  greatly  enriched  through  that  process  of  division  of 
labor  among  medical  men  that  we  know  as  the  rise  of  specialism  in 
medicine.  Physicians  and  surgeons  interested  in  special  domains  have 
devised  a  whole  series  of  new  methods  of  observation  and  of  experiment, 
some  of  them  involving  the  skillful  use  of  instruments  of  a  greater  or 
less  degree  of  complexity.  The  technique  of  ophthalmoscopy,  of  re- 
fraction, of  otoscopy,  of  laryngoscopy,  of  esophagoscopy,  of  sigmoidos- 
copy, of  cystoscopy,  of  ureteral  catheterization,  and  the  like,  can  be 
learned  by  any  medical  man  of  intelligence,  but  mastership  in  these 
practical-technical  procedures  is  not  easy  and  requires  a  practical  experi- 
ence extending  over  a  considerable  time  for  its  acquisition.  The  result 
has  been  that  many  men  have  decided  to  "  specialize  "  in  order  that  they 


662  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

may  acquire  extraordinary  skill  in  the  diagnosis  and  treatment  of  dis- 
ease in  certain  regions  or  systems  of  the  body.  Thus,  to-day, 
besides  the  general  practitioner,  general  internist,  and  surgeon, 
we  see  professional  men  who  are  known  as  specialists  in  diseases 
of  children,  in  diseases  of  the  eyes,  in  diseases  of  the  ears, 
nose,  and  throat,  in  tuberculosis,  in  cardio-vascular  diseases,  in  dis- 
eases of  the  blood,  in  dentistry,  in  diseases  of  the  digestive  tract, 
in  gynecology,  in  urology,  in  orthopedics,  in  neurology,  in  psychiatry, 
in  dermatology,  in  endocrinology,  in  roentgenology,  and  in  clinical  chem- 
istry. No  single  person  can  therefore  hope  to  be  equally  familiar  with 
the  facts  and  principles  and  equally  skillful  in  applying  the  practical- 
technical  methods  of  all  these  specialties;  indeed,  few  men  pretend  to 
mastery  of  more  than  two  or  three  of  them.  If  the  internist  is  to  avail 
himself,  then,  of  all  the  diagnostic  methods  that  are  helpful,  he  must,  in 
certain  cases  at  least,  call  specialists  in  particular  domains  to  aid  him 
by  sharing  in  the  labor  of  accumulating  clinical  data. 

Among  the  pressing  problems  that  medical  educators  of  the  present 
time  have  to  solve  are  those  concerned  with  the  training  of  both  general 
practitioners  and  specialists,  and  with  the  making  of  arrangements  that 
will  insure  the  mutual  helpfulness  of  these  two  groups  in  the  diagnosis 
of  disease  and  the  treatment  of  the  sick.  The  ordinary  curriculum  of  the 
medical  school  is  now  so  crowded  that  the  medical  student  in  his  under- 
graduate course,  though  he  receives  a  thorough  training  in  history  taking 
and  in  the  general  methods  of  physical  and  psychical  diagnosis,  can 
scarcely  be  expected  to  do  more  in  addition  than  to  learn  the  main  facts 
and  principles  of  the  several  medical  and  surgical  specialties  and  to 
acquire  enough  first-hand  experience  with  special  instruments  like  the 
ophthalmoscope,  the  nasopharyngoscope,  the  bronchoscope,  the  cysto- 
scope,  the  ureteral  catheter,  the  polygraph,  and  the  electrocardiograph  to 
permit  him  to  understand  their  uses  and  to  make  clear  to  him  the 
importance  of  their  application  as  aids  to  diagnosis  in  certain  special 
cases.  There  is  not  time  in  the  undergraduate  medical  course  for  the 
student  to  obtain  the  experience  in  any  special  domain  that  justifies 
him  in  regarding  himself  as  a  medical  or  surgical  specialist.  To  become 
an  expert  ophthalmologist,  urologist,  orthopedist,  neurologist,  or 
dermatologist,  he  must  undertake  special  work  extending  over  a  con- 
siderable period  after  his  graduation.  The  post-graduate  schools  are 
attempting  to  supply  opportunities  for  quickly  gaining  the  experience 
in  specialistic  work  that  will  make  men  competent,  but  as  yet  only  a 
beginning  in  this  direction  has  been  made.  There  is  urgent  need  for 
the  endowment  of  post-graduate  schools  with  suitable  hospitals  attached 
in  which  men  may  be  adequately  trained  in  the  work  of  the  several 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        663 

specialties.  At  present  a  young  physician  who  desires  to  specialize  in 
some  one  branch  does  best  to  attach  himself  as  an  assistant  to  a  real 
expert  in  the  subject  that  interests  him.  Opportunities  of  this  sort  are, 
of  necessity,  limited  in  number.  It  is  owing  to  the  paucity  of  such 
opportunities  for  intensive  post-graduate  studies  in  the  special  branches, 
despite  the  growing  demand  for  specialists  in  practice,  that  so  much 
pseudo-specialism  now  exists.  For  the  sake  of  the  suffering  public  as 
well  as  for  the  advancement  of  scientific  medicine  this  situation  must  be 
squarely  faced  by  medical  educators,  by  philanthropists,  and  by  the 
state,  its  defects  recognized  and  the  remedy  sought  and  applied. 

The  sick  should  reap  the  advantages  that  can  be  derived  from  the 
division  of  labor  in  medicine.  Laymen  have  discovered  that  some 
expert  specialists  exist,  but  they  are  unable  often  to  distinguish  the  true 
expert  from  the  pseudo-expert.  Having  found  that  the  general  prac- 
titioner is  not  always  wise  enough  to  seek  the  aid  of  a  true  specialist 
when  his  help  is  needed,  laymen  have  tended  more  and  more  to  apply 
directly  to  medical  or  surgical  specialists  when  they  themselves  believe 
that  their  malady  pertains  to  a  special  domain.  This  tendency  can  only 
be  harmful  not  only  to  the  patients  themselves  but  also  to  the  general 
practitioners  and,  in  the  long  run,  to  the  specialists.  In  order  that  the 
best  work  shall  be  done  in  diagnosis  and  therapy,  some  means  of 
coordinating  the  activities  of  general  practitioners  and  specialists  so 
that  the  best  results  will  be  obtained  for  all  must  be  found.  A  general 
practitioner  or  an  internist,  who  works  alone  and  who  does  not  call  to 
his  aid,  at  least  in  an  obscure  case,  men  who  have  had  special  training 
in  particular  domains  will  be  sure  to  miss  facts  that  are  highly  important 
for  a  complete  understanding  of  his  patient's  condition.  On  the  other 
hand,  the  specialist  who  works  by  himself,  taking  care  of  all  patients  who 
apply  to  him,  whether  or  not  they  are  referred  to  him  by  a  general  prac- 
titioner or  an  internist,  is  in  danger  of  forgetting  that  he  studies  only 
one  part  of  the  body  and  that,  though  he  may  find  abnormalities  in  his 
special  domain,  these  may  be  less  important  for  the  patient's  whole  state 
than  are  other  abnormalities  that  exist  unknown  to  him  in  other  domains. 
Some  way  or  another  must  be  found  by  which  patients  may  profit  by 
the  division  of  medicine  into  specialties  while  at  the  same  time  they  are 
protected  from  the  dangers  of  a  one-sided  study. 

The  medical  profession  is  now  trying  to  solve  the  problem  just 
stated  by  means  of  "  group  work  "  or  "  cooperative  diagnosis."  Diag- 
nostic groups  are  being  formed  in  which  each  member  of  the  group 
possesses  special  skill  in  some  particular  kind  of  work  and  one  member, 
who  acts  as  integrator,  tries  to  combine  the  single  parts  into  a  properly 
proportioned  whole.     In  this  connection  I  can  perhaps  not  do  better 


664         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

than  to  quote  from  an  address  given  before  the  New  York  Academy  of 
Medicine  in  191 7,  in  which  I  briefly  discussed  this  topic  of  cooperative 
diagnosis  in  obscure  cases  requiring  the  intensive  exploration  of  several 
special  domains : 

"  The  integrator  should  preferably  be  a  person  who,  though  perhaps 
especially  skilled  in  some  one  branch,  is  rather  encyclopedic  in  training 
and  comprehension,  sympathetic  and  tolerably  familiar  with  work  in  all 
the  divisions  of  modern  medicine  and  surgery,  free  from  prejudices, 
disciplined  by  sufficient  experience  in  hospital  wards,  in  clinical  labora- 
tories, and  in  the  autopsy  room,  and  blessed  with  that  common  sense 
that  is,  in  the  last  analysis,  largely  a  sense  of  proportion. 

"  Specialism,  thus  resulting  in  the  orderly  cooperation  of  the  mem- 
bers of  a  group,  instead  of  acting  as  a  disintegrating  force,  may  be  made 
to  contribute  to  a  higher  unity,  most  helpful  both  to  the  public  and  to 
the  profession.  With  organization  in  groups  of  the  kind  mentioned,  it 
would  matter  but  little  to  whom  the  patient  applied  for  diagnosis;  if 
the  integrator  be  applied  to  first,  he  will  secure  the  reports  from  other 
members  of  the  group  before  undertaking  the  integration;  if  a  specialist 
in  some  single  anatomical  domain  be  applied  to  first,  he  may  make  his 
own  examination,  refer  the  patient  to  the  integrator  for  the  conduct  of 
the  rest  of  the  study,  and  receive  from  the  latter  the  full  and  propor- 
tionate diagnostic  report  upon  which  a  rational  therapy  can  be  planned. 
Obviously,  mutual  confidence  and  good-will  must  prevail  among  the 
members  of  such  a  group.  Such  groups  already  exist  and  the  number 
of  them  is,  I  believe,  destined  rapidly  to  increase.  The  older  competitive 
methods  must  give  way  to  the  newer  cooperative  methods  in  medicine 
as  in  all  other  walks  of  life.  Nothing  could  be  more  unfortunate,  how- 
ever, than  the  formation  of  cliques  when  arranging  for  group  work  in 
diagnosis,  and  I  would  warn  emphatically  against  this  danger.  It  is 
obvious,  I  think,  that  such  a  system  as  I  am  referring  to  does  not  restrict 
any  specialist  or  any  integrator  to  activity  in  a  single  group;  there  is 
no  reason  why  either  should  not  participate  in  the  activities  of  several 
different  or  overlapping  cooperating  groups,  the  important  points  being 
that  the  group  at  work  on  any  single  case  shall  be  so  constituted  as  to 
insure,  first,  expert  study  in  each  of  the  several  bodily  domains  in  which 
there  is  an  indication  of  the  need  of  special  study,  and,  secondly,  a  com- 
bination of  the  parts  of  the  study  into  a  well-balanced  whole,  the  sys- 
tematic analysis  being  followed  by  an  adequate  synthesis. 

"  Now,  in  most  cases,  there  is,  of  course,  no  necessity  of  examination 
by  every  member  of  a  large  group  of  specialists.  In  addition  to  the 
anamnesis,  the  general  physical  and  psychical  examination,  the  routine 
laboratory   tests   and   X-ray   tests   already   mentioned,    there    may   be 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS         665 

required  special  examinations  in  only  one  or  two  anatomical  domains. 
In  obscure  cases,  however,  and  especially  in  instances  of  chronic  infec- 
tions necessitating  the  search  for  hidden  foci,  we  may  feel  the  need  of 
calling  upon  a  number  of  experts  for  aid.  How  many  cases  of  chronic 
infectious  arthritis,  for  example,  progress  for  months  because  the  diag- 
nostic studies  have  been  limited  to  too  few  domains,  when  more  com- 
plete studies  might  have  located  the  primary  foci  that  were  responsible? 
No  one  can  lay  down  hard  and  fast  rules  as  to  how  extensive  a  study 
should  be.  The  judgment  and  experience  of  the  one  who  has  the  general 
conduct  of  the  study  in  charge  must  decide  after  the  anamnesis  has 
been  recorded  and  the  general  physical  and  psychical  examination  has 
been  made.  The  main  thing  is  that  he  who  conducts  the  study  shall 
be  sensitive  to  the  problems  that  confront  him  and  know  how  to  apply 
the  best  skill  in  attacking  and  solving  them.  The  greater  the  talents  and 
experience  of  the  integrator,  the  better  his  insight  and  discernment,  the 
more  likely  he  will  be  to  have  a  proper  sense  of  the  indicative  importance 
of  the  various  features  of  a  puzzling  case.  The  greater  his  familiarity 
with  the  making  of  general  diagnostic  surveys,  the  more  he  will  avoid 
requesting  examinations  that  are  wholly  superfluous,  the  less  likely  he 
will  be  to  neglect  a  test  that  is  essential  in  any  single  case.  The  taking 
of  too  much  pains  in  one  case  may  be  foolish;  the  taking  of  too  little 
in  another  may  be  disastrous," 

Just  how  such  cooperative  diagnosis  will  ultimately  be  carried  out 
is,  as  yet,  somewhat  doubtful.  The  general  hospitals  have  been  grad- 
ually working  toward  it,  but  there  must  be  much  reorganization  of  these 
hospitals  if  the  best  results  of  cooperative  diagnosis  are  to  be  obtained 
and,  especially,  the  men  working  in  such  hospitals  must  be  brought  to 
an  understanding  of  the  advantages  of  such  group  work  and  must  be 
taught  how  to  organize  for  it  and  how  the  organization  must  be  man- 
aged in  order  that  it  may  be  efficient.  Aside  from  the  work  of  the 
general  hospitals,  cooperative  diagnostic  clinics  have  already  arisen  in 
different  places  in  the  United  States.  The  Mayo  Clinic  at  Rochester, 
Minnesota,  and  the  "  Pay  Diagnostic  Clinics  "  of  Boston  and  of  San 
Francisco  are  notable  examples.  In  many  places,  group  diagnosis  is 
carried  on  in  office  buildings  by  cooperating  physicians,  surgeons,  and 
specialists.  In  most  places,  however,  the  physician  making  a  general 
diagnostic  survey  still  has  to  send  his  patients  to  specialists  in  his  own 
town  or  even  to  those  in  more  distant  places  for  reports  of  intensive 
studies  in  special  domains.  A  general  practitioner  when  isolated  in  the 
country  has  to  do  the  best  he  can  without  such  cooperative  work,  and 
it  has  been  matter  of  surprise  and  pleasure  to  me  to  see  how  successful 
some  men  so  situated  are  in  the  general  diagnostic  surveys  that  they 


666         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

make.  Certainly  recent  medical  graduates,  who  have  had  a  thorough 
training  in  general  medicine,  surgery,  and  the  more  important  medical 
specialties,  as  well  as  in  laboratory  work  and  in  X-ray  work,  may, 
single-handed,  do  general  diagnostic  work  of  a  very  high  order  before 
they  become  too  busy,  though  even  these  men  could  do  still  better  work 
if  they  were  members  of  groups  in  which  a  division  of  labor  was  ar- 
ranged for.  It  seems  to  me  possible  that,  in  country  districts,  county 
hospitals,  in  which  the  work  of  cooperative  diagnosis  by  a  differentiated 
staff  will  be  undertaken  and  be  supported  in  part  by  public  funds,  may 
ultimately  be  organized.  Great  convenience  for  patients  and  for  physi- 
cians results  from  arranging  for  the  combination  of  the  differentiated 
diagnostic  activities  under  a  single  roof.  Centers  in  which  cooperative 
diagnostic  groups  can  work  effectively  seem  destined  to  grow  in  numbers 
and  in  public  esteem. 

The  cost  of  making  a  complete  diagnostic  survey  in  an  obscure  case 
requiring  the  cooperative  activities  of  a  general  internist  and  a  group 
of  specialists  is  an  item  that  merits  special  comment.  Unless  ways  can 
be  devised  for  bringing  the  cost  of  such  an  examination  comfortably 
within  the  means  of  all  that  require  it,  many  who  would  benefit  by  it 
will  be  compelled  to  do  without  it.  It  must,  of  course,  be  borne  in  mind 
that  the  great  bulk  of  medical  practice  as  done  at  present  is  carried  on 
without  the  making  of  a  general  diagnostic  survey  of  the  patients  in 
the  sense  of  this  discussion.  Indeed,  for  the  host  of  minor  ailments 
from  which  patients  suffer,  it  would  be  superfluous  to  undertake  the 
kind  of  general  diagnostic  survey  here  described.  An  elaborate  investi- 
gation of  every  minor  ailment  would  be  a  waste  of  the  patient's  time 
and  money  and  of  the  physician's  time  and  energy.  Among  his  patients 
the  physician  of  good  judgment  will  have  but  little  difficulty,  however, 
in  selecting  a  certain  number  that,  for  their  own  sake  as  well  as  for 
the  reputation  of  the  practitioner,  should  be  advised  to  undergo  a  general 
diagnostic  survey.  Those  selected  would  include  the  class  of  patients 
ordinarily  referred  to  internists,  surgeons,  and  medical  and  surgical 
specialists  for  consultation.  For  this  group  of  cases  it  is  desirable  that 
methods  for  making  quickly,  efficiently  and  inexpensively  a  general 
diagnostic  survey  shall  be  evolved.  Thus  far  the  well-to-do  are  becom- 
ing provided  for  in  the  private  wards  of  general  hospitals  and  in  private 
group-clinics,  and  the  poor  are  also  being  very  well  looked  after  in  the 
public  wards  of  those  general  hospitals  in  which  the  method  of  group 
diagnosis  has  been  introduced.  Provision  has  yet  to  be  made,  however, 
for  satisfactory  group  diagnosis  for  those  patients  whose  incomes  pre- 
clude the  use  of  free  dispensaries  or  of  the  public  wards  of  hospitals, 
but  are  not  sufficiently  large  to  permit  them  to  pay  the  usual  fees  for  the 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        d^^y 

more  expensive  diagnostic  survey  carried  on  in  private  wards  of  hos- 
pitals or  in  private  clinics  by  an  expert  integrator  cooperating  with  a 
group  of  consulting  specialists.  Though  groups  of  the  latter  sort  study 
a  certain  number  of  patients  of  small  or  of  moderate  means,  reducing 
the  fees  charged  for  the  whole  study  to  an  amount  that  is  no  hardship 
or  inconvenience  to  the  patients,  no  matter  what  their  incomes  are,  still 
the  amount  of  such  work  that  can  be  done  by  the  groups  thus  far  organ- 
ized is  relatively  small  in  proportion  to  the  public  need.  Moreover, 
many  patients  who  would  benefit  by  a  general  diagnostic  survey  hesitate 
to  avail  themselves  of  an  organization  in  which  the  ordinary  charge  for 
a  general  study  is  beyond  their  means,  even  though  the  total  charge  be 
willingly  reduced  to  a  merely  nominal  sum.  In  Boston  and  in  San 
Francisco  an  effort  has  been  made  to  provide  for  this  class  of  patients 
in  the  "  Pay  Clinics  "  that  have  there  been  organized,  and  at  the  Mayo 
Clinic  the  cost  of  an  elaborate  general  diagnostic  study  has  been  kept 
low.  There  would  seem  to  be  room  in  all  large  cities  for  organizations 
of  young  men  who  are  gradually  making  their  reputations  to  be  of 
service  in  this  connection.  This  is  work,  too,  for  which  community 
funds  justifiably  might  be  expended.  Industrial  establishments,  towns, 
cities,  counties  and  states  might  do  well  to  foster  organizations  for 
group  diagnosis,  making  financial  appropriations  to  aid  them,  and  pro- 
viding for  regulation  and  supervision  that  would  insure  efficient  and 
ethical  conduct.  The  methods  of  the  business  organizer  and  business 
manager  might  well  be  adopted  here,  not  for  exploitation,  but  for  the 
welfare  and  protection  of  the  sick. 

The  filing  of  reports  of  the  results  of  intensive  examinations  of 
special  domains  completes  the  preliminary  collection  of  data  necessary 
for  the  localization  and  definition  of  the  diagnostic  problem.  The  facts 
accumulated  include  the  records  of  the  anamnesis,  of  the  general 
physical  and  psychical  examination,  of  the  laboratory  tests  made,  of  the 
X-ray  tests  made,  and  of  the  intensive  examinations  made  in  special 
domains.  These  facts  may  now  be  summarized  and  arranged  in  groups, 
according  to  the  anatomical-physiological  systems  to  which  they  pertain. 
The  time  will  then  have  arrived  for  brooding  over  the  data  gathered 
and  for  allowing  the  things  that  we  have  observed  to  bring  into  our 
minds  things  that  we  have  not  observed.  Suggestions  of  solution  of 
the  diagnostic  problem  ought  to  begin  to  occur  to  us.  We  are  ready, 
therefore,  to  enter  upon  the  third  stage  of  the  diagnostic  procedure. 


668         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

Stage  III:  Summarizing  and  Arranging  the  Data  Accumulated, 

Pondering  Them  and  Recording  the  Diagnostic 

Suggestions  That  Occur  to  the  Mind 

In  order  that  suggestions  of  possible  solution  of  our  diagnostic 
problem  may  occur  to  our  minds,  we  must  weigh  mentally  the  facts 
that  we  have  accumulated  in  recording  the  anamnesis,  in  making  the 
general  physical  and  psychical  examination,  in  the  making  of  laboratory 
tests  and  of  X-ray  tests,  and  on  intensive  examination  of  special  domains. 
We  stop  observing  and  experimenting  for  a  time  in  order  that  there 
may  occur  to  us  ideas  of  what  the  things  already  observed  may  mean. 
We  begin  to  draw  inferences  from  the  facts. 

Consideration  of  the  facts  with  this  purpose  in  view  is  greatly  facili- 
tated, however,  (i)  by  making  a  preliminary  summary  and  (2)  by 
rearranging  the  facts  in  a  systematic  way. 

Thus,  in  order  that  one  may  take  in  at  a  glance  the  positive  abnormal 
findings  in  the  case,  it  will  be  found  convenient,  first,  to  summarize 
these  findings  under  the  general  headings  that  correspond  to  their  mode 
of  accumulation. 

Summary  of  Abnormal  Findings. 

1.  Anamnesis. 

2.  General  physical  and  psychical  examination. 

3.  Laboratory  tests. 

4.  Roentgenological  examinations. 

5.  Intensive  examinations  in  special  domains. 

From  the  large  mass  of  data  accumulated  one  selects  for  this  pre- 
liminary summary  only  the  points  that  represent  definite  deviations  from 
normal  conditions.  This  makes  for  brevity  and  for  ease  of  survey,  and 
the  summary  serves  as  a  valuable  control  of  the  fact  accumulation,  for 
one  can,  from  looking  over  it  quickly,  discover  whether  any  important 
method  of  examination  suggested  by  the  results  of  the  anamnesis  and  of 
the  general  physical  and  psychical  examination  has  been  omitted  in  the 
study  as  carried  on  up  to  this  point.  Furthermore,  when  the  more 
important  facts  are  thus  closely  crowded  together  in  a  summary,  defects 
in  the  reports  of  suggestive  symptoms  or  of  physical  findings  or  of 
special  examinations  may  be  easily  recognized  and  remedied  before  one 
entertains  ideas  of  interpretation.  One  may  find,  for  example,  that  the 
report  of  a  dental  consultation,  or  of  an  X-ray  examination  that  has 
been  requested,  has  not  been  sent  in;  or  one  may,  on  this  quick  review, 
become  cognizant  that  he  has  neglected,  on  outlining  the  course  of  the 
study,  to  include  the  making  of  some  observation,  or  of  some  special 
test,  the  necessity  for  which  was  clearly  pointed  to  by  one  of  the  symp- 
toms of  which  the  patient  complained  or  by  one  of  the  signs  recorded 
at  the  first  physical  examination. 

The  data  accumulated  may  next  be  rearranged  according  to  the 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS         669 

anatomical-physiological  domains  to  which  they  reasonably  may  be  sup- 
posed to  be  related.  This  is  another  method  of  finding  out  whether 
our  observations  and  experiments  have  been  sufficiently  inclusive.  For 
this  rearrangement  of  the  facts  in  a  systematic  way  I,  myself,  make  use 
of  a  single  sheet  upon  which  the  following  form  is  printed,  sufficient 
space  being  provided  for  the  inclusion  of  the  various  symptoms  and 
signs  that  are  likely  to  be  met  with  in  any  case  in  connection  with  any 
one  of  the  anatomical-physiological  systems: 

Data  Rearranged  According  to  the  Syste7ns  to  Which  They  May  Be  Related. 

Name :  Age :  Body  Temperature : 

Chief  Complaints : 

Time  and  Mode  of  Onset: 

Habits : 

Infections : 

Operations ;  Traumata : 

Respiratory  System : 

Circulatory  System : 

Blood  and  Hematopoietic  System :  R.  B.  C.  Hb.  W,  B.  C.  WaR. 

PMN.  PME.  SM.         LM.         Tr. 

Platelets  Bacteria  Parasites 

Digestive  System :   Free  HCl  Total  Acidity  Occ.  Blood        Stool 

Urine  and  Urogenital  System:  Urine:  Sp.  gr.  Alba  Sugar        Cvla. 

W.  B.  C.  R.  B.  C.  Phthalein  Output 

Locomotor  System : 
Nervous  System  and  Sense  Organs : 
Metabolism  and  Endocrine  System : 
Remarks : 

In  this  systematic  rearrangement  of  the  more  important  data,  we 
include  both  positive  and  negative  findings,  jotting  them  down  in  as 
brief  form  as  is  compatible  with  quick  apprehension,  use  being  made  of 
various  symbols  for  purposes  of  abbreviation.  Thus  under  the  head- 
ing "  Circulatory  System  "  will  be  placed  symptoms  such  as  dyspnea, 
palpitation,  precordial  pain,  and  retrosternal  oppression,  should  they  be 
complained  of,  any  physical  signs  referable  to  the  heart  and  blood  ves- 
sels (e.g.  pulse  rate,  arrhythmias,  systolic  and  diastolic  blood  pressure, 
position  and  character  of  apex  beat,  abnormal  pulsations,  heart  mur- 
murs, cyanosis,  thickened  vessels,  arcus  senilis,  or  edema),  teleroent- 
genographic  measurements  and  electrocardiagraphic  results,  if  they  have 
been  recorded.  Under  the  heading  "  Metabolism  and  Endocrine  Sys- 
tem "  will  be  placed  deviations  from  calculated  ideal  weight,  notes  from 
the  anamnesis  regarding  gouty  attacks  or  a  gouty  family  history,  dia- 
betic symptoms,  struma,  tachycardia,  fine  tremor,  eye  signs  common 
in  the  thyreopathies,  abnormalities  in  the  distribution  of  hair,  pigmenta- 
tions, condition  of  the  acra,  and  the  like.  When  placing  a  symptom  like 
dyspnea,  it  may  be  well  to  include  it  not  only  under  "  Respiratory 
System  "  but  also  under  "  Circulatory  System  "  and  under  "  Metabo- 
lism "  unless  it  has  already  become  clear  to  what  division  the  symptom 
predominantly  belongs.     Each  integrator  in  rearranging  the  data  will 


670         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

adopt  or  devise  symbols  and  abbreviations  that,  though  they  are  imme- 
diately intelligible,  save  space. 

It  will  have  been  observed  that,  in  making  such  a  systematic  re- 
arrangement of  the  findings,  the  integrator  has  already  begun  to  draw 
certain  inferences  and  to  make  a  series  of  particular  judgments,  for 
the  assignment  of  given  symptoms  or  signs  to  definite  anatomical- 
physiological  domains  is  based  upon  knowledge,  or  prior  experience, 
concerning  the  possible  meanings  of  those  symptoms  or  signs.  The 
actual  process  of  clinical  diagnosis  includes  a  search  for  clues,  or  marks, 
and  the  formation  of  judgments  regarding  the  meaning  of  such  clues,  or 
marks  as  are  discovered.  The  rearrangement  of  these  clinical  marks 
in  groups  according  to  the  several  anatomical-physiological  systems  to 
which  they  presumably  pertain  takes  the  facts  out  of  the  quarantine 
hitherto  imposed  upon  them;  isolation  of  the  single  facts  gives  way  to 
association  in  groups  as  the  integrator  works  at  this  stage  of  the  diag- 
nostic procedure.  The  materials  thus  dealt  with  prepare  the  way  for  the 
perception  of  further  relations  that  may  exist  among  the  facts.  Thus, 
the  data  pertaining  to  each  anatomical-physiological  domain  may  next 
be  considered  as  a  whole  and  judgments  formed  concerning  their  mean- 
ing and  origin;  later  on,  the  relationship  of  the  disturbances  discovered 
in  one  anatomical-physiological  domain  to  those  found  to  exist  in  other 
domains  may  be  sought  for,  with  the  idea  of  uniting  two  things  in  a 
third  that  is  the  foundation  of  the  relationship  {fundamentum  relationis 
of  the  schoolmen).  Such  partial  considerations  as  those  just  mentioned 
are  necessary  preliminaries  to  the  localization  of  disease  processes,  and 
the  assignment  of  place  to  the  pathological  phenomena  is,  in  turn,  neces- 
sarily antecedent  to  a  proper  understanding  of  the  nature  and  cause 
of  these  phenomena;  reflection  upon  the  state  of  the  patient  as  a  whole, 
which  we  depend  upon  for  supplying  us  with  suggestions  regarding  the 
ultimate  solution  of  our  total  diagnostic  problem,  can  be  advantageously 
entered  upon  only  after  we  have  made  a  long  series  of  partial  considera- 
tions and  particular  judgments  and  have  already  surmounted  a  num- 
ber of  local  and  minor  diagnostic  difficulties. 

It  may  be  worth  while  to  advert  for  a  moment  to  the  kind  of  mental 
process  we  make  use  of  when  we  have  reached  the  stage  of  our  diag- 
nostic investigation  in  which  we  allow  ourselves  to  entertain  suggestions 
of  explanation  of  the  data  that  we  have  gathered,  summarized  and  sys- 
tematically rearranged.  We  begin  now  to  draw  larger  inferences,  to 
form  diagnostic  hypotheses,  to  harbor  interpretative  ideas.  Observa- 
tion and  experimentation,  hitherto  our  main  tasks,  are  now  temporarily 
stopped.  We  begin  to  think  and  to  make  use  of  the  creative  imagination. 
With  feet  firmly  fixed  upon  a  basis  of  the  facts  observed,  we  try  to  pass 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS         671 

by  induction,  or  by  deduction,  to  inference.  We  brood  over  the  ma- 
terials that  we  have  selected  and  prepared  in  the  hope  that  things  that 
we  have  observed  will  lead  us  to  ideas  of  things  that  cannot  be  ob- 
served. Contemplating  the  contents  of  our  experience  with  the  patient 
before  us,  we  try  to  assimilate  them  with  the  contents  of  our  own  past 
experience  (gained  by  studying  patients  and  the  medical  sciences)  and  of 
the  experience  of  other  physicians  as  reported  to  us  in  medical  literature, 
believing  that,  on  such  assimilation,  suggestions  will  arise  in  our  minds 
that  we  may  tentatively  entertain  concerning  things  that  our  own  present 
experience,  by  itself,  does  not  hold.  In  other  words,  we  now  call  upon  our 
powers  of  reflection  to  make  contributions  beyond  what  our  sense  organs 
are  able  to  yield  to  us.  Were  it  not  for  this  capacity  of  the  mind  to 
make  leaps  from  facts  to  ideas,  we  should  never  go  far  in  the  process  of 
clinical  diagnosis.  The  mind  of  the  diagnostician  must  bound  forward 
by  a  leap,  or  by  a  succession  of  leaps,  from  the  observed  clinical  facts  to 
ideas  of  what  these  facts  may  mean.  Thus,  the  integrating  internist 
must  be  a  mental  gymnast;  and  he  has  to  learn  that  expertness  in  the 
form  of  intellectual  activity  here  described  can  scarcely  be  expected 
except  after  long  experience,  carefully  directed.  The  regulation  of 
the  conditions  under  which  the  function  of  suggestion  is  allowed  to 
take  place  is  of  the  highest  importance.  Unless  due  care  and  attention 
have  been  exercised  in  the  accumulation,  selection,  and  arrangement 
of  the  facts  from  the  consideration  of  which  the  diagnostic 
suggestions  are  to  emerge,  the  conditions  under  which  the  creative 
imagination  has  to  work  will  be  faulty.  Even  when  the  con- 
ditions have  been  adequately  regulated,  a  proper  use  of  the  function 
of  suggestion  implies  the  cultivation  of  both  courage  and  caution 
as  habits  of  mind.  We  should  be  bold  enough  to  entertain  several 
rival  diagnostic  conjectures  that  we  test  for  validity,  but  we 
must  be  cautious  enough  to  make  sure  that  only  hypotheses  that  are 
found,  on  testing  them,  to  be  valid  are  accepted  as  diagnostic  conclusions. 
One  sometimes  hears  medical  men,  well-meaning  enough  but  innocent  of 
any  real  acquaintance  with  the  manner  of  working  of  the  mind  of  the 
scientist,  declare  that  "  there  is  no  place  for  imagination,  or  for  hy- 
pothesis, in  diagnostic  work  "  and  that  "  the  real  diagnostician  should 
content  himself  with  facts."  But  the  truth  is  that  everyone  who  does 
good  work  in  clinical  diagnosis  is  compelled,  whether  he  is  cognizant 
of  it  or  not,  to  form  hypotheses  before  he  arrives  at  satisfactory  diag- 
nostic conclusions,  A  study  of  the  conditions  under  which  hypotheses 
should  be  permitted  to  arise  and  a  knowledge  of  how  to  deal  with  these 
hypotheses  once  they  have  arisen  in  the  mind  would  seem,  then,  to  be 
indispensable  for  the  higher  walks  of  clinical  diagnosis. 


672  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

Returning  now  to  the  actual  occurrence  of  diagnostic  suggestions  to 
the  mind  when  studying  given  cases,  we  may  illustrate,  by  citing  a  few 
examples,  how  suggestions  of  meaning  begin  to  arise  on  looking  over  the 
groups  of  symptoms  and  signs  after  their  systematic  tabulation  in  groups 
corresponding  to  single  domains.  Thus,  if  one  finds  recorded  under 
the  "  Digestive  System "  morning  diarrhea  and  the  absence  of  free 
hydrochloric  acid  in  the  stomach  juice,  he  will  at  once  think  of  an 
achylia  gastrica  and  of  its  possible  relationship  to  a  chronic  gastritis, 
to  an  oral  sepsis,  or  to  a  pernicious  anemia.  Or,  if  under  the  same 
system,  one  finds  recorded  a  gastric  hyperacidity,  tenderness  in  the 
right  lower  quadrant,  displacement  of  the  stomach,  markedly  downward 
and  to  the  right  in  the  roentgenogram,  and  the  history  of  recurring 
attacks  of  indigestion,  he  will  think  of  the  possible  existence  of  some 
lesion  in  the  right  lower  quadrant  of  the  abdomen,  say  a  chronic  ap- 
pendix. Or  if  there  be  recorded,  in  an  obese  person  above  the  age  of 
40,  a  gastric  subacidity,  a  history  of  pain  in  the  right  upper  quadrant 
of  the  abdomen  (especially  after  riding  horseback,  after  a  night's  ride 
in  a  sleeper,  or  after  an  automobile  tour),  of  transitory  attacks  of 
jaundice,  and  of  an  earlier  attack  of  typhoid  fever,  the  idea 
of  some  gall-bladder  trouble,  probably  gall-stones,  will  occur  to  the 
mind.  Or,  if  one  find  recorded  anorexia,  an  absence  of  free  hydro- 
chloric acid  in  the  stomach  juice,  occult  blood  in  the  stool,  and  a 
definite  filling  defect  in  the  roentgenogram  of  the  stomach,  the  exist- 
ence of  carcinoma  ventriculi  will  at  once  be  suspected.  Or,  again,  if 
under  the  "  Circulatory  System,"  one  sees  noted  a  retromanubrial  dull- 
ness, a  systolic  blood  pressure  of  170,  a  diastolic  pressure  of  90,  thick- 
ened radial  arteries,  an  arcus  senilis,  a  widened  aorta  or  a  transverse 
position  of  the  heart  in  the  X-ray,  he  will  think  at  once  of  an  arterio- 
sclerotic process;  or,  if  a  definite  thrill  be  palpable  in  the  region  of  the 
apex  of  the  heart  and  an  asynchronism  of  the  second  sounds  be  audible 
in  the  pulmonic  area,  the  first  sound  at  the  apex  being  abrupt,  the  exist- 
ence of  a  mitral  stenosis  due  to  an  earlier  thrombo-endocarditis  will  no 
doubt  suggest  itself  as  a  diagnostic  idea.  Or,  if  at  the  wrist  a  perpetually 
irregular  pulse  be  felt  and  the  record  of  the  electrocardiogram  shows  a 
good  many  small  waves  arising  in  the  atrium  for  every  ventricular  com- 
plex, the  existence  of  atrial  fibrillation  will  at  once  be  thought  of  and 
a  search  for  its  etiology  suggested.  Or,  if  the  pulse  rate  be  120  and 
there  be  no  heart  murmurs  or  marked  enlargement  of  the  heart,  one  will 
think  at  once  of  the  possibility  of  a  thyreopathy  as  an  explanation  and 
seek  for  corroborative  data.  Or,  if,  again,  the  pulse  rate  be  48,  one 
would  leap  to  the  idea  of  the  existence  of  a  conduction-disturbance  in 
the  atrioventricular  bundle  of  the  heart  and  would  also  find  himself 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        673 

wondering  whether  this  disturbance  had  its  origin  in  some  organic 
lesion  within  the  heart  itself,  or  had  been  due  to  a  depression  of  the 
function  of  the  bundle  through  vagus  influences  excited  from  a  dis- 
tance (intestinal  irritation;  increased  intracranial  pressure). 

If,  to  take  another  example,  under  the  "  Urogenital  System,"  in  a 
woman  of  forty-two,  one  find  recorded  a  prolonged  metrorrhagia,  say 
a  flow  of  ten  days  each  month,  along  with  enlargement  of  the  uterus, 
he  will  probably  think  of  myomatosis  with  endometritis,  and  of  car- 
cinoma uteri,  as  rival  explanatory  hypotheses,  each  of  which  is  rigorously 
to  be  tested  for  validity.  If,  under  the  "  Nervous  System,"  the  data 
include  nystagmus,  loss  of  abdominal  reflexes,  and  scanning  speech,  the 
integrator  will  think  at  once  of  lesions  disseminated  through  the  nervous 
system,  the  exact  topography  and  nature  of  which  he  may  try  to  deter- 
mine. Or,  if  under  the  "  Hemapoietic  System,"  he  finds  jotted  down  a 
profound  anemia  with  leukopenia,  with  a  differential  count  of  the  white 
corpuscles  showing  a  relative  lymphocytosis  of  94  per  cent.,  along  with 
enlargement  of  the  spleen  and  with  slight  enlargement  of  the  cervical 
lymph  glands,  the  experienced  internist  may  think  of  the  possible  exist- 
ence of  an  aleukemic  lymphadenosis,  of  a  pernicious  anemia,  or  of  an 
anemia  occurring  in  the  course  of  a  syphilis.  As  these  examples  illus- 
trate, we  deal  at  this  stage  separately  with  the  symptoms  and  signs  that 
pertain  to  each  one  of  the  several  anatomical-physiological  domains, 
cudgeling  our  brains  for  cues  of  possible  meaning.  When  a  group  of 
signs  and  symptoms  are  present  in  a  single  domain,  one  should  not  be  too 
easily  satisfied  with  the  occurrence  to  the  mind  of  a  single  descriptive 
or  explanatory  hypothesis.  Several  possible  hypotheses  should  be 
allowed  to  present  themselves  if  they  will  and  these  should  be  pitted 
against  one  another  as  lusty  rivals  that  are  to  be  given  opportunity  to 
fight  for  supremacy.  Hundreds  of  examples  of  syndromes  might  easily 
be  given,  were  there  need,  but  those  mentioned  will  doubtless  suffice  to 
illustrate  the  mode  of  occurrence  of  diagnostic  ideas  to  a  mind  that  is 
pondering  the  symptoms  and  signs  that  have  been  referred  to  a  given 
anatomical-physiological  system. 

As  has  been  repeatedly  emphasized  in  this  article,  on  encouraging 
diagnostic  suggestions  to  which  a  consideration  of  the  facts  as 
summarized  and  rearranged  is  to  give  rise,  one  tries  to  make  scientific 
use  of  the  imagination,  a  process  that  makes  demands  not  only 
upon  the  intellect  but  also  upon  the  affective-conative  functions  (the  feel- 
ings and  the  will).  From  one's  previous  knowledge  and  experience  he 
attempts  to  recognize  in  the  group  of  facts  before  him  either  some  well- 
known  uniformity  of  sequence  or  some  easily  identifiable  uniformity  of 
coexistence;  only  when  no  well-known  one  can  be  discovered  by  him. 


674  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

does  he  permit  himself  to  think  that  he  may  be  dealing  with  some  new, 
or  hitherto  undescribed,  syndrome.  The  aim  of  every  scientific  worker 
is  to  discover  scientific  laws  to  which  the  facts  that  he  accumulates  will 
conform.  The  scientific  diagnostician  desires  also  to  summarize  in  a 
single  statement,  or  in  some  brief  formula,  the  disease  process  by  which 
he  is  confronted  and  from  which  the  whole  group  of  facts  that  he  has 
collected  regarding  the  patient  can  be  seen  to  flow.  Out  of  a  vast  com- 
plexity of  anamnestic  data,  of  physical  signs,  of  chemical  reactions,  and 
of  biological  tests,  he  strives  to  derive  a  unity,  to  detect  the  "  one  in 
the  many";  by  means  of  a  disciplined  imagination  he  attempts  to 
formulate  conceptions  in  which  the  whole  range  of  facts  may  be  re- 
sumed. He  sets  up  groups  of  tentative  or  hypothetical  conclusions  that 
he  is  to  scrutinize  thoroughly  and  to  examine  adversely  before  admitting 
their  validity.  In  order  that  a  clinician  may  make  a  diagnosis  as  com- 
plete and  as  satisfactory  as  is  possible  in  the  state  of  medical  knowledge 
that  exists  in  his  time,  he  must  obviously,  in  addition  to  native  ability, 
have  a  wide  acquaintance  with  the  main  facts  of  all  the  medical  sciences 
and  he  must  have  already  become  familiar  with  the  classifications  of 
groups  of  facts  and  with  the  descriptive  formulae  that  have  hitherto 
been  made  use  of  by  other  clinical  workers.  A  certain  esthetic  element 
doubtless  enters  into  the  experience.  The  brief  statement  under  which 
a  large  number  of  facts,  or  of  perceptions  and  conceptions,  is  resumed 
must  be  felt  to  be  adequate. 

It  was  Karl  Pearson,  I  believe,  who  emphasized  that  the  continual 
gratification  of  the  esthetic  judgment  is  one  of  the  chief  delights  of 
the  pursuit  of  science.  That  this  is  true  in  the  science  of  diagnosis, 
will  be  admitted  by  every  advanced  worker.  The  more  comprehensive 
the  diagnostic  study  made,  and  the  more  complete  the  understanding 
of  the  relationships  of  alterations  of  form  and  function  to  causes 
arrived  at,  the  greater  the  esthetic  appeal  to  the  mind  of  the  diag- 
nostician of  philosophic  turn.  This  is  why  he,  in  making  a  clinical 
diagnosis,  strives  to  arouse  satisfactory  suggestions  of  solution  of  his 
diagnostic  problems  by  thinking  systematically,  first,  of  the  possible 
pathological-physiological  significance,  secondly,  of  the  possible  patho- 
logical-anatomical basis,  and  thirdly,  of  the  possible  etiological  and 
pathogenetic  relationships  of  a  given  fact  or  group  of  facts.  He  thus 
secures  his  ideas  of  syndromes  made  up  of  functional  disturbances,  of 
the  lesions  present  and  their  topographical  relationships,  of  the  nature 
of  the  disease  processes  that  are  going  on  in  his  patients  and  of  their 
etiology.  The  several  ideas  that  thus  occur  to  him  must,  he  knows, 
be  subjected  to  such  rigid  criticism  that  the  conclusions  he  finally 
arrives  at  will  be  equally  valid  for  the  minds  of  other  clinicians  who 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS        675 

work  in  the  same  way.  Intellect,  emotion,  and  will, — all  contribute,  then, 
their  share  to  the  mental  operations  of  this  stage  of  the  diagnostic  inquiry. 
One  may  ask  the  question,  What  reason  have  we  to  believe  that  dif- 
ferent physicians,  even  when  using  the  method  of  science,  will,  in  study- 
ing a  given  case,  arrive  at  similar,  or  identical,  diagnostic  conclusions? 
The  reason  why  there  can  be,  and  often  is,  agreement  in  opinion  among 
diagnosticians  lies,  one  must  believe,  in  a  similarity  of  behavior  of 
normally  constituted  minds.  To  the  normal  mind,  the  world  outside — 
the  world  of  phenomena — presents  itself  in  a  certain  way.  The  per- 
ceptive powers  of  normal  minds  must  be  very  similar  to  one  another. 
The  same  must  be  true  of  the  reflective  activities  of  the  mind  in  normal 
persons.  The  mechanisms  of  association  and  of  logical  inference  work 
similarly  in  different  healthy  people  with  the  result  that  the  mental 
contents  of  stored  sense-impressions  and  of  conceptions  will  be  suffi- 
ciently similar  to  yield  almost  identical  results  in  the  same  circumstances. 
The  normal  mind,  when  bombarded  by  a  series  of  sense-impressions  or 
perceptions,  associates  them  with  sense-impressions  that  have  been  stored 
in  the  memory;  it  combines  these  into  conceptions  or  constructs;  a  train 
of  thought  Is  set  up  through  association  and  the  recognition  of  rela- 
tionships; conceptions  are  formed  and  inferences  begin  to  be  drawn. 
Were  it  not  that  normal  human  beings  perceive  the  same  phenomena 
and  reflect  upon  them  in  very  similar  manner,  there  could  be  no  agree- 
ment regarding  diagnostic  conclusions,  indeed  there  could  be  no  such 
thing  as  science  of  any  sort.  As  Pearson  has  well  put  it,  "  Human  minds 
are,  within  limits,  all  receiving  and  sifting  machines  of  one  type." 
Minds  that  in  their  activities  deviate  too  much  from  this  normal  type, 
we  call  disordered  or  insane.  Within  the  range  of  normality,  however, 
there  is  opportunity  for  considerable  variation  in  activity.  Minds  that 
we  call  normal,  though  very  similar  in  their  activity,  are  by  no  means 
identical.  We  have  abundant  proof  of  this  in  the  diagnostic  suggestions 
that  occur  to  diflferent  physicians  who  have  had  similar  training  and 
equality  of  opportunity  for  acquiring  experience.  To  one  mind,  ideas 
of  meaning  may  come  easily  and  promptly,  to  another  they  come  slowly 
and  with  difficulty.  To  one  mind,  a  group  of  facts  may  quickly  give 
rise  to  several  ideas  of  possible  meaning;  to  another  mind,  the  stimula- 
tion by  the  same  group  of  facts  is  barren  of  response.  It  is  desirable 
of  course  that  the  number  and  range  of  ideas  excited  by  the  facts  ac- 
cumulated will  suffice  for  the  purpose  of  the  study;  there  should  not  be 
too  few  of  them  and  there  should  not  be  too  many.  Moreover,  the 
quality  of  the  ideas  of  solution  that  are  aroused  is  even  more  significant 
than  the  promptness  with  which  they  come,  or  the  abundance  of  the 
supply.    One  physician's  mind  may  respond  speedily  with  an  abundance 


676  THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

of  suggestions  and  yet  these  suggestions  may  be  inferior  for  the  purpose 
in  hand  to  those  that  arise  in  a  mind  whose  response  is  slower  but  more 
profound.  Rapidity  of  response  is  of  course  good  in  itself,  but  mere 
quickness  will  not  compensate  for  either  excessive  prolificity  or  super- 
ficiality. A  physician  should,  as  far  as  possible,  train  his  mind  to  make 
quick,  balanced,  and  deep  responses  when  he  contemplates  groups  of 
clinical  facts,  in  order  that  he  may  be  supplied  with  enough  worthy 
and  substantial  diagnostic  ideas  to  test  systematically  for  validity.  Good 
native  ability  and  prolonged  training  are  essential  for  the  best  kind  of 
diagnostic  work.  Though  minds  differ,  the  differences  within  normal 
limits  are  less  important  than  the  resemblances.  Normally  constituted 
minds  are  so  nearly  alike  in  their  workings  that  diagnosticians  of  normal 
mental  endowment  who  are  well-educated  in  the  contents  and  methods 
of  the  medical  sciences,  on  studying  similar  pathological  conditions, 
will,  we  may  feel  sure,  arrive  at  similar  conclusions. 

In  making  a  general  diagnostic  survey  of  a  patient,  the  aim  is  to  get 
as  complete  an  understanding  as  possible  of  the  functioning  of  the 
whole  man  in  his  physical,  psychical,  and  social  aspects  with  the  object 
of  being  of  real  help  to  him  in  improving  his  condition.  As  has  been 
pointed  out,  the  group  of  facts  pertaining  to  each  of  the  bodily  domains 
(respiratory,  circulatory,  digestive,  etc.)  is  first  appealed  to  for  sug- 
gestions of  meaning  and  for  calling  forth  in  our  mind  ideas  of  simi- 
larity, of  coexistence,  or  of  sequence.  We  should  not  stop,  however, 
with  the  recording  of  suggestions  based  upon  the  consideration  of  the 
data  pertaining  to  these  several  systems,  but  should  next  turn  to  a  sur- 
vey of  the  whole  series  of  suggestions  that  have  thus  arisen.  For  after 
testing  systemic  ideas  for  their  validity,  we  want  to  know  the  rela- 
tive importance  of  the  several  partial  diagnoses  that  are  found  to  be 
valid  for  an  understanding  of  the  condition  of  the  patient  as  a  whole. 
Until  this  general  survey  has  been  undertaken  and  completed,  no  final 
unified  diagnostic  conclusion  with  suitable  ordination  of  all  the  factors 
in  the  case  can  be  arrived  at.  By  keeping  the  purpose  of  the  diagnostic 
study  vividly  in  mind,  namely,  the  desire  to  find  out  what  is  wrong  with 
the  patient,  in  order  to  direct  him  how  best  to  act,  we  shall  find  a  suitable 
guide  to  the  whole  diagnostic  procedure;  this  directing  principle  will 
enforce  orderliness  in  the  application  of  our  methods,  and  it  will  give 
steadiness  and  continuity  to  our  thinking  as  it  moves  toward  its  goal. 

Stage  IV:  The  Elaboration  by  Reasoning  of  the  Implications  of 
Each  Diagnostic  Suggestion  or  Inference 

Before  yielding  assent  to  any  suggestion  that  has  issued  from  a 
consideration  of  the  facts  after  they  have  been  summarized  and  ar- 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS      677 

ranged,  no  matter  how  plausible  such  a  suggestion  may  seem,  it  should 
have  been  traced  to  its  full  consequences  and  its  validity  carefully  tested. 
The  acceptance  of  an  idea  as  valid  before  it  has  been  elaborated  so  that 
its  full  bearings  may  be  clearly  seen  and  compared  with  the  facts  that 
exist  is  the  mark  of  an  uncritical  thinker.  There  is  no  room  in  clinical 
diagnosis  for  light-hearted  and  over-ready  belief.  Any  tendency  to 
infer  wildly,  rashly,  or  fallaciously  must  be  vigorously  combated.  One 
should  familiarize  himself  with  the  canons  of  legitimate  inference  and 
make  sure  that  he  is  governed  by  them.  When  resorting  to  this  reason- 
ing process  in  which  all  the  implications  of  each  suggestion  deemed 
worthy  of  testing  are  developed  and  are  compared  with  the  facts  that 
have  been  accumulated  regarding  the  patient,  it  will  frequently  occur 
that  the  diagnostician  will  discover  the  need  of  supplementing  his  first 
store  of  facts  by  further  observation  or  by  further  experiment.  It  may 
even  be  necessary  to  apply  methods  other  than  those  that  have  been 
used  in  a  search  for  new  materials  to  support,  or  to  render  untenable, 
an  idea  of  interpretation  that  has  occurred  to  the  mind.  It  is  only  after 
we  have  entirely  unfolded  a  diagnostic  idea  in  detail  that  we  can  com- 
pare the  several  particulars  that  compose  it  with  the  facts  as  we  have 
observed  them  and  decide  whether  or  not  sameness  can  be  recognized 
and  identity  established.  When  the  facts  observed  are  found  to  be  in  ac- 
cord with  the  implications  of  a  diagnostic  suggestion  as  fully  reasoned 
out,  we  accept  the  suggestion  as  valid  and  have  a  feeling  of  belief  in  it. 
This  process  of  developing  the  implications  of  diagnostic  suggestions 
by  reasoning  may  be  illustrated  by  considering,  as  examples,  the  diag- 
nostic suggestions  that  occur  to  us  as  solutions  of  the  diagnostic  problem 
presented  by  a  patient  who  exhibits  an  acute  febrile  process  with  leuko- 
penia. The  patient,  let  us  say,  has  complained  of  headache,  of  pain  in 
his  back,  of  loss  of  appetite,  and  of  disinclination  for  exertion.  The 
temperature  of  his  body  has  been  found  to  be  102.5°  Fahrenheit,  his 
pulse  rate  is  84  and  the  pulse  is  slightly  dicrotic.  A  few  rhonchi  are 
audible  over  the  lungs,  the  spleen  is  palpable,  and  the  white-cell  count 
of  the  blood  is  4,800.  When  confronted  by  this  group  of  facts,  the 
diagnostician  will  at  once  think  of  infectious  processes  associated  with 
splenomegaly  and  leukopenia,  and  he  will  recall  that  two  of  the  com- 
moner infections  of  this  sort  are  typhoid  fever  and  malaria.  His  next 
step  will  be  to  develop  the  implications  of  each  of  these  two  diagnostic 
suggestions  by  reasoning.  He  will  say  to  himself.  "If  the  suggestion 
of  typhoid  fever  be  correct,  we  should  find  in  studying  the  history  of 
this  patient's  illness  an  insidious  onset  of  the  symptoms,  a  characteristic 
temperature  curve,  a  relative  bradycardia,  an  initial  bronchitis,  head- 
ache, anorexia,  palpable  spleen,  perhaps  rose  spots,  a  leukopenia,   an 


6r8         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

early  bacillaemia,  an  absence  of  coryza  and  herpes,  an  epidemiological 
record  that  gives  the  clue  to  the  source  of  a  bacillus  typhosus  in  the 
case,  the  presence  of  the  typhoid  bacillus  in  plate-cultures  made  from 
the  feces  on  the  Drigalski-Conradi  medium,  or  on  Endo's  fuchsin  agar, 
the  presence  of  specific  agglutinins  in  the  blood  after  the  disease  has 
lasted  for  a  certain  length  of  time,  etc."  He  will  also  elaborate  the 
suggestion  of  malarial  fever  and  will  say  to  himself,  "If  this  patient 
has  malaria,  his  temperature-chart  should  be  that  of  either  an  inter- 
mittent fever  (if  it  be  a  tertian  or  a  quartan  case),  or  a  continuous  or 
remittent  fever  (if  it  be  an  estivo-autumnal  case)  ;  the  patient  will  have 
had  chills,  sweats,  headaches,  anorexia,  palpable  spleen,  herpes  labialis, 
leukopenia,  anemia,  a  history  of  exposure  to  the  bite  of  an  Anopheles 
mosquito,  and  perhaps  neuralgic  pains;  in  his  blood,  the  presence  of 
malarial  parasites  should  be  demonstrable,  and  pigment  containing 
leukocytes  may  also  be  discernible;  marked  amelioration  of  the  symp- 
toms will  follow  the  administration  of  quinine,  etc."  If  the  diagnos- 
tician be  a  careful  and  experienced  worker,  he  will  have  thought  not 
only  of  the  commoner  infections  associated  with  leukopenia,  such  as 
typhoid  fever  and  malaria,  but  also  of  the  somewhat  less  common  con- 
ditions so  associated,  such  as  paratyphoid  fever,  measles,  mumps, 
glanders,  and  dengue.  It  will  have  occurred  to  him  still  further  that 
leukopenia  is  sometimes  met  with  in  certain  very  severe  forms  of  infec- 
tion, like  pneumonia  and  septicemia,  that  in  ordinary  circumstances  are 
associated  with  leukocytosis.  He  will  then  develop  the  full  implications 
of  these  diagnostic  ideas  also.  These  several  diagnostic  suggestions,  thus 
fully  developed  as  to  their  implications,  will  be  looked  upon  by  him  as 
so  many  intellectual  keys  with  which  he  will  successively  try  to  fit  the  lock. 
If  none  of  the  keys  he  has  forged  is  found  to  fit,  he  must  try  some 
modification  of  one  of  them  or  make  still  other  keys  to  try.  It  may 
be  that  some  complicating  process  of  a  secondary  nature  is  changing  the 
clinical  picture  so  that  it  deviates  from  type.  When,  in  a  case,  a  survey 
of  the  data  as  a  whole  suggests  the  existence  of  a  certain  disease-process, 
one  should  give  this  process  careful  consideration,  even  though  some 
of  the  data  recorded  seem  to  be  inconsistent  with  it.  Thus,  if  the  symp- 
toms and  signs  on  the  whole  suggest  the  existence  of  typhoid  fever,  one 
should  not  throw  this  diagnostic  suggestion  into  the  discard  simply 
because  a  leukocytosis  is  present,  for,  although  leukopenia  is  the  rule 
in  typhoid  fever,  we  do  sometimes  find  a  leukocytosis  in  that  disease, 
owing  to  a  complicating  pyogenic  process  (phlebitis,  pneumonia,  chole- 
cystitis, etc.).  Or,  to  take  another  example,  if  the  knee-jerks  and  ankle- 
jerks  are  absent  in  a  patient,  and  anesthesias  and  paresthesias  of  his 
lower  extremities  have  been  recorded,  the  diagnostician  will  not  rule  out 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS       679 

the  idea  of  tabes  dorsalis,  at  once,  simply  because  an  Argyll-Robertson 
pupil  is  not  present,  but  will  still  keep  this  diagnostic  suggestion  in  mind 
along  with  other  conjectures  of  possible  solutions  of  the  diagnostic 
problem  (funicular  myelitis;  polyneuritis;  etc.).  He  will  then  reason 
each  of  the  suggestions  out  fully  as  to  its  implications,  and,  if  necessary, 
will  make  further  observations  or  experiments  that  will  decide  whether 
identity  exists.  He  may  require  to  extend  the  blood  examination,  to 
undertake  the  examination  of  the  cerebrospinal  fluid,  or  to  map  out 
the  exact  topography  of  the  sensory  disturbances.  It  may  even  be  neces- 
sary considerably  to  enlarge  the  anamnestic  record  in  the  case.  If  there 
be  no  anemia,  if  the  cerebrospinal  fluid  yield  a  positive  Wassermann 
reaction  and  contain  many  lymphocytes  and  more  globulin  than  normal, 
if  the  topography  of  the  sensory  disturbance  be  segmental  in  type,  and 
if  the  revised  anamnesis  reveal  the  history  of  luetic  infection,  of  periods 
when  lancinating  pains  occurred  and  show  the  absence  of  any  abuse  of 
alcohol  and  of  any  poisoning  by  lead,  arsenic,  or  other  substances  that 
cause  neuritis,  the  idea  of  tabes  dorsalis  as  a  satisfactory  diagnosis  may 
be  accepted  as  valid  even  though  no  Argyll-Robertson  pupil  be  demon- 
strable. Thus  a  diagnostic  suggestion  that,  on  elaboration,  seems  to  be 
inconsistent  with  some  of  the  data  present,  may,  on  modification,  be 
found  to  be  adequate  as  a  solution  of  a  diagnostic  problem. 

The  original  diagnostic  suggestions  that  come  up  in  our  minds  are 
always  inchoate;  they  require  to  be  developed.  From  principles  that 
have  already  been  established  in  medicine  and  with  which  we  have 
become  familiar  through  our  earlier  clinical  experience  and  through  our 
study  of  medical  books  and  journals,  we  deduce  the  fullness  and  com- 
pleteness of  their  meaning.  The  data  accumulated  by  the  analytical 
processes  of  the  anamnesis,  and  by  means  of  the  general  physical  and 
psychical  examination,  the  laboratory  tests,  the  X-ray  tests,  and  the 
special  tests,  suggest  to  us,  when  we  brood  over  them,  wholes  into  which 
they  may  be  synthesized.  Such  suggested  wholes  are  then  again  dis- 
integrated by  a  reasoning  process  of  deduction  into  their  known  con- 
stituent parts.  Further  observation  and  experimentation  may  then  be 
required  before  identity  can  be  established  between  one  of  these  sug- 
gested wholes  with  its  constituent  elements  and  the  actual  whole  to 
which  the  symptoms  and  signs  in  our  patient  really  belong.  Indeed, 
one  of  the  great  advantages  of  the  consideration  of  all  the  possible 
bearings  of  the  general  diagnostic  notions  that  we  tentatively  harbor  is 
that  it  often  leads  us  to  expand  substantially  our  collection  of  particular 
data.  The  full  development,  by  reasoning,  of  all  the  implications  of 
the  diagnostic  suggestions  that  occur  to  us  is,  then,  an  essential  part  of 
the  diagnostic  procedure. 


68o         THE  RATIONALE  OF  CLINICAL  DIAGNOSIS 

Stage  V :  The  Testing  of  Diagnostic  Suggestions  {Elaborated 

by    Reasoning)  for  Their  Validity  and  Arriving 

at  Diagnostic  Conclusions  or  Beliefs 

It  has  been  repeatedly  emphasized  that  before  we  accept  a  diagnostic 
suggestion,  inference,  or  hypothesis,  after  developing  its  bearings  and 
implications,  as  a  true  explanation  or  description  of  the  facts  in  a  case, 
we  must  test  it  carefully  for  its  vaHdity.  Having  found  out  by  a  process 
of  deductive  reasoning  precisely  what  it  implies,  we  must  demonstrate 
that  there  is  identity  between  its  implications  and  the  actual  data  that 
we  have  accumulated,  or  can  accumulate,  regarding  the  patient.  If  the 
diagnostic  suggestion  as  developed  by  ratiocination  be  found  to  be  out 
of  accord  with  the  facts  collectable  we  dare  not  give  credence  to  it. 
Accordance  in  composition  with  what  has  been,  or  can  be,  observed  is 
the  sole  real  test  for  the  validity  of  a  diagnostic  suggestion. 

If,  on  looking  over  our  amassed  data,  we  find  some  single  fact  that 
seems  to  be  in  absolute  conflict  with  some  implication  of  our  reasoned- 
out  suggestion,  though  the  other  facts  are  in  entire  conformity,  we  shall 
do  well  to  question  the  accuracy  of  our  observation  on  the  one  hand 
and  the  flawlessness  of  our  reasoning  on  the  other.  If  the  discordant 
fact  be  confirmed  by  a  second  observation  and  if  it  can  be  shown  that 
there  has  been  no  fallacy  in  reasoning  out  the  implications  of  a  diagnostic 
suggestion,  the  latter,  unless  it  can  be  so  modified  as  to  do  away  with 
the  discrepancy,  must  be  regarded  as  untenable.  Any  absolute  conflict 
between  clinical  facts  and  diagnostic  suggestion  is  fatal  to  the  sugges- 
tion as  a  whole,  for  in  the  phrase  of  the  logicians,  "  falsus  in  uno,  falsus 
in  omni."  It  must  surely  be  quite  clear  that  what  is  true  of  one  thing 
must  be  true  also  of  its  equivalent. 

In  this  last,  or  fifth  stage,  of  the  diagnostic  procedure  we  have  to 
deal,  then,  with  the  verification,  or  corroboration,  of  our  conjectural 
ideas.  It  will  be  recalled  that  in  the  third  stage  of  our  inquiry  we 
allowed  the  particular  facts  that  we  had  accumulated  regarding  the 
patient  to  call  forth  in  our  minds  suggestions  of  a  general  nature  that 
might  explain  these  facts,  or  that  might  at  least  classify  them  under  a 
common  head;  we  there  tried,  by  an  inductive  process,  to  pass  from 
certain  results  wr  consequences  (our  collected  data)  to  some  general 
conceptions  from  which  they  might  be  presumed  to  flow.  It  will  also 
be  remembered  that  in  the  fourth  stage  of  our  study  these  suppositional 
general  conceptions  were,  by  a  process  of  deduction,  reasoned  out  fully 
as  to  their  bearings  and  implications ;  through  ratiocination  we  deter- 
mined what  particular  clinical  facts  or  consequences  ought  to  be  present 
in  the  patient  if  the  general  ideas  were  valid.  Now  we  come  to  the 
last  stage  of  the  diagnostic  inquiry,  in  which  our  task  consists  in  com- 


ACTUAL  PROCESS  OF  CLINICAL  DIAGNOSIS         68i 

paring  the  whole  meaning  embodied  in  the  diagnostic  suggestion,  that 
is,  the  whole  of  the  consequences  that  flow  from  it,  with  the  actual 
clinical  facts  that  we  have  gathered,  or  that  we  can  gather  by  further 
observation  and  experimentation.  We  have,  at  this  stage,  to  trace  out 
fully  the  degree  of  similarity  that  obtains  between  the  facts  that  exist 
and  the  facts  that  should  exist  if  the  ideas  that  have  occurred  to  us  are 
true.  We  must  ascertain  whether  there  is  a  sufficient  degree  of  likeness 
or  sameness  to  justify  the  acceptance  of  the  idea  that  we  have  tenta- 
tively entertained  and  rationally  elaborated;  and  if  we  have  provisionally 
considered  other  diagnostic  ideas  as  rivals  to  it,  we  must  demonstrate 
that  the  distinguishing  criteria  of  these  rivals  are  absent.  Unless  a 
diagnostic  idea  as  fully  reasoned  out  can  be  verified  we  dare  not  believe 
it  to  be  true. 

The  secondary  observation  and  experimentation  stimulated  by  our 
attempt  to  establish  identity  between  observable  particulars  and  the  im- 
plications of  a  tentative  idea  may  strengthen  or  weaken  the  diagnostic 
conjecture  and  result  in  corroborating  it,  or  in  refuting  it.  Thus  in  the 
case  of  infection  with  fever,  leukopenia,  and  palpable  spleen  to  which 
we  have  referred,  it  may  be  found  possible  on  reexamination  of  the 
patient  to  discover  that  we  had  previously  overlooked  a  roseola;  or  we 
may  find  on  the  patient's  lip  a  slight  herpes  that  had  not  been  noticed 
at  the  first  examination  or  that  had  been  passed  over  as  insignificant; 
or  in  a  blood  culture  made  in  bile-bouillon  we  may  be  able  to  grow  a 
motile  bacillus  which,  on  being  tested,  turns  out  to  be  the  bacillus 
para  typhosus ;  or  again,  on  making  another  careful  search  of  a  stained 
smear  of  the  blood,  we  may  find  a  single  crescent-shaped  malarial  para- 
site, or  some  small  intracorpuscular  forms  that  earlier  had  escaped 
observation;  or,  a  week  or  two  after  the  first  examination,  during  which 
time  the  diagnosis  has  remained  in  doubt,  we  may  become  able  to 
demonstrate  specific  agglutinins  for  bacillus  typhosus  in  the  blood, 
though  the  Widal  reaction  had  been  negative  at  the  first  examination. 
Thus,  where  neither  corroboration  nor  entire  rejection  may  be  justifiable 
on  comparison  of  the  facts  originally  collected  with  the  implications  of 
the  conjectural  idea  of  diagnosis  entertained,  additions  that  will  bring 
a  decision  may  sometimes  be  made  to  the  clinical  data. 

As  long  as  the  data  are  insufficient  for  the  determination  of  identity 
between  the  facts  of  experience  and  the  reasoned-out  implications  of 
a  diagnostic  idea,  the  scientific  diagnostician  will  reserve  his  judgment. 
And  though  doubt  as  to  diagnosis  will  seem  intolerable  to  him  as  long 
as  a  chance  of  a  justifiable  decision  remains  open,  he  will  nevertheless 
often  be  compelled  to  suspend  a  conclusion  when  a  more  ignorant,  or 
a  less  cautious,  mind,  unwilling  to  bear  a  painful  feeling  of  incapacity. 


682  THE  RATIONAj:.E  OF  CLINICAL  DIAGNOSIS 

will  indulge  in  a  positive  decision  and  advance  in  a  wrong  direction. 
The  only  safe  way  to  arrive  at  accurate  diagnostic  conclusions  or  beliefs 
is  to  follow  the  slow  process  that  has  been  indicated,  namely,  fact 
accumulation  by  observation  and  experiment,  lying  with  the  facts  that 
tentative  ideas  of  solution  may  be  engendered,  reasoning  these  out  fully 
as  to  their  implications,  comparing  these  implications  with  the  facts  to 
see  whether  or  not  identity  can  be  established,  if  necessary  making 
further  observations  or  experiments  to  extend  the  facts,  and  testing  one 
suggestion  after  another  until  at  least  some  one  of  them  can  be  cor- 
roborated and  accepted  as  valid;  then,  and  not  until  then,  should  a 
diagnostician  permit  himself  to  feel  that  his  problem  has  been  solved. 

The  best  diagnostic  brain,  fortified  by  a  large  experience,  will  some- 
times make  mistakes  in  diagnosis,  even  when  all  the  precautions  that 
have  been  referred  to  have  been  observed.  Indeed,  it  has  been  among 
the  highest  type  of  clinicians,  from  the  earliest  times  on,  that  can  be 
found  most  often  the  evidences  of  willingness  to  acknowledge  that 
"  experience  is  fallacious  and  judgment  difficult."  No  medical  man  is  so 
expert  or  so  careful  that  he  never  arrives  at  diagnostic  conclusions  that, 
later  on,  have  to  be  revised.  Exploratory  operations  on  the  living  and 
complete  autopsies  upon  fatal  cases,  are  most  salutary  correctives  of 
diagnostic  jauntiness.  The  diagnostician  who  follows  his  patients  to 
the  operating  room,  or  their  bodies,  should  they  die,  to  the  morgue, 
learns  lessons  in  modesty  and  takes  the  best  course  for  the  avoidance 
of  presumption  on  the  one  hand  and  undue  diffidence  on  the  other.  The 
physician  who  conscientiously  applies  the  method  of  science  to  clinical 
diagnosis,  who  recognizes  how  difficult  diagnosis  in  a  given  case  may 
be,  who  tries  to  make  accurate  observations  himself,  who  is  willing 
sometimes  to  enlist  the  aid  of  expert  observers  in  special  domains  in 
the  collection  of  data,  who  deduces  fully  the  consequences  that  flow 
from  any  diagnostic  suggestions  that  occur  to  him,  and  who  insists 
upon  accordance  between  these  reasoned  consequences  and  the  clinical 
facts  before  he  permits  himself  to  arrive  at  a  diagnostic  conclusion, 
can  feel  sure  that  he  is  working  in  the  right  way  and  can  know  that, 
as  he  grows  in  knowledge  and  experience,  he  will  become  an  ever  more 
expert  diagnostician. 

The  extent  to  which  a  diagnostic  study  is  carried  will  depend  partly 
upon  the  purpose  for  which  the  study  is  made  and  partly  upon  the  natural 
endowment  and  the  experience  of  the  man  making  it.  The  purpose  of  the 
general  practitioner  varies  somewhat  from  that  of  the  consulting  phy- 
sician, and  the  purpose  of  the  latter  is  dififerent  to  a  certain  extent  from 
that  of  the  man  who  devotes  his  life  to  original  investigation.  The 
particular  aim  that  the  diagnostician  has  in  view  (welfare  of  the  single 


BIBLIOGRAPHY  683 

patient;  or  additions  to  knowledge  that  may  contribute  to  the  welfare 
of  future  generations)  will,  in  some  degree,  determine  the  methods  of 
clinical  investigation  employed  and  the  scope  of  the  diagnostic  inquiry. 

The  natural  capacity,  the  experience,  and  the  ideals  of  the  diag- 
nostician will  have  their  influence  upon  the  work  that  he  does.  They 
will  reveal  themselves  in  problem  recognition,  in  the  practical  technique 
of  fact  accumulation,  in  creative  imagination,  in  reasoning  power,  in 
verification,  in  philosophic  grasp,  and  in  esthetic  appreciation.  It  is  well, 
now  and  then,  perhaps  to  take  stock  of  the  personal  qualities  that  make 
for  success  in  diagnosis.  What  Faraday  said  of  the  philosopher 
is  very  applicable  to  the  diagnostician  of  the  higher  type.  He  "  should  be 
a  man  willing  to  listen  to  every  suggestion,  but  determined  to  judge  for 
himself.  He  should  not  be  biased  by  appearances;  have  no  favorite 
hypothesis;  be  of  no  school;  and  in  doctrine  have  no  master.  He  should 
not  be  a  respecter  of  persons,  but  of  things.  Truth  should  be  his  primary 
object.  If  to  these  qualities  be  added  industry,  he  may  indeed  hope  to 
walk  within  the  veil  of  the  temple  of  nature." 

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BALDWIN,  J.  M.:  Thought  and  Things.  3  vols.  New  York:  The  Macmillan 
Company. 

BARKER,  L.  P.:  The  General  Diagnostic  Study  by  the  Internist,  etc.  N.  Y. 
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BOSANQUET,  B.:  The  Essentials  of  Logic.  New  York:  The  Macmillan  Com- 
pany, 1895. 

BRADLEY,  F.  H.:  The  Principles  of  Logic  (Anastatic  Reprint).  New  York: 
G.  E.  Stechert  &  Co.,  1912. 

CABOT,  R.  C:  Differential  Diagnosis.  Philadelphia:  W.  B.  Saunders  Com- 
pany, 191 1. 

DAVIS,  M.  M. :  Group  Medicine,  Am.  Jour.  Public  Health,  Boston,  1919. 

DEWEY,  J.:  How  We  Think.    Boston:  D.  C.  Heath  &  Co.,  1916. 

FOLLETT,  M.  P.:  The  New  State:  Group  Organization  the  Solution  of  Popular 
Government.    London:  Longmans,  Green  &  Co.,  191 8. 

FRENCH,  H.:  Index  of  Differential  Diagnosis.  New  York:  Wm.  Wood  &  Co.. 
1917. 

HORNE,  H.  H.:  Psychological  Principles  of  Education:  A  Study  m  the  Science 
of  Education.    New  York :  The  Macmillan  Company,  1906. 

JAMES,  W.:  The  Principles  of  Psychology.  2  vols.  New  York:  Henry  Holt 
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JEVONS,  W.  S.:  The  Principles  of  Science:  A  Treatise  on  Logic  and  Scientific 
Method.    New  York:  Tlie  Macmillan  Company,  1900. 

JONES,  BENCE:  The  Life  and  Letters  of  Faraday.  2  vols.  London:  Long- 
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LASEGUE,  C:   De  la  logique   scientifique   et  de   ses  applications  medicales. 

Paris:  Arch.  gen.  de  med.,  1868,  6.  s.,  XI,  715-732. 
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Methuen  &  Co.,  1915. 
MACKENZIE,  J.:  Symptoms  and  Their  Interpretation.     New  York:  P.  B. 

Hoeber,  1914. 
MILL,  J.  S. :  System  of  Logic,  Ratiocinative  and  Inductive.    8th  ed.    New  York: 

Harper  &  Brothers,  1900. 
MILLER,  J.  E.:  The  Psychology  of  Thinking.     New  York:  The  Macmillan 

Company,  1917. 
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MULLER,  F. :  Der  Ausbau  der  klinischen  Untersuchungsmethoden.  Ztschr.  f. 

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OESTERLEN,  F.:  Medical  Logic.     Transl.  and  edited  by  G.  Whitley,  M.D. 

London:  Sydenham  Society,  1855. 
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1911. 


CHAPTER  XVI 
TESTS    OF    FUNCTION    IN    INTERNAL    MEDICINE 

By  henry  a.  christian 

Table  of  Contents 

Introduction 685 

Table  of  Normal  Laboratory  Values 686 

Blood,  Plasma  or  Serum  Values 686 

Urine  Values 690 

Liver  Function  Tests 691 

Renal  Function  Tests 692 

Hematologic  Values 693 

Spinal  Fluid  Values 693 

Miscellaneous  Values 694 

Introduction 

When  body  structures  function  within  the  Umits  of  what  is  considered  normal 
variation,  and  when  the  function  of  each  structure  is  correlated  with  that  of  all 
the  other  structures  in  the  body,  so  that  these  structures  are  coordinated  in  their 
activities  to  produce  an  harmonious  total  activity,  we  consider  the  result  to  be 
what  we  term  health.  In  contrast,  dysfunction  of  any  structure  or  structures  of 
the  body,  not  compensated  by  that  of  other  structures,  results  in  what  we  term 
sickness  or  disease.  Such  dysfunctions  of  body  structures  are  of  primal  importance 
in  clinical  internal  medicine  or  the  study  of  medical  patients  who  have  the  sjnnp- 
toms  or  signs  of  sickness  or  disease. 

Body  dysfunctions,  as  referred  to  m  the  preceding  paragraph,  express  them- 
selves in  symptoms  and  signs  of  sickness  or  disease,  and  their  recognition  and 
evaluation  are  necessary  to  diagnosis  and  treatment.  For  an  adequate  under- 
standing and  evaluation  of  such  symptoms  and  signs  knowledge  of  the  function 
of  the  various  body  structures  is  needed,  so  that  the  internist  may  know  which 
are  and  which  are  not  functioning  ^\athin  normal  limits  as  determined  from  the 
accumulated  recordings  of  many  studies.  Many  methods  for  such  studies  or,  as 
we  term  them,  tests  of  function  have  been  developed  and  apphed  to  human 
beings,  both  well  and  sick.  Repetition  has  determined  for  each  test  what  we 
regard  as  the  limits  of  normality.  In  drawing  conclusions  for  the  individual  it 
needs  to  be  recognized  that  one  form  of  decrease  in  function  often  can  and  is 

COPYRIGHT  1947   BY  THE  OXFORD    UNIVERSITY   PRESS,   NEW   YORK,  INC. 

685 


686        TESTS  OF  FUNCTION  IN  INTERNAL  MEDICINE 

compensated  for  by  an  increased  functional  activity  of  some  other  body  struc- 
ture, so  that  not  one  but  several  tests  of  function  are  needed  to  evaluate  what 
seem  to  be  departures  from  normal  hmits  of  function  affecting  significantly  the 
individual. 

In  the  period  of  early  editions  of  Oxford  Medicine  many  tests  of  function 
were  so  new  that  they  had  not  been  incorporated  in  easily  available  descriptions 
of  many  diseases.  Consequently  it  seemed  desirable  to  describe  in  some  detail 
in  one  place  numerous  tests  of  function,  which  had  been  recognized  as  useful  in 
the  examination  of  individual  patients.  Their  use  then  constituted  something 
new  in  internal  medicine;  the  results  obtained  from  them  were  yielding  important 
data,  not  otherwise  readily  attainable,  applicable  to  diagnosis  and  treatment. 
At  present  tests  of  fimction  have  become  so  generally  used  and  the  figures  and 
other  data  obtained  from  them  so  well  kno\vn,  that  no  longer  is  a  separate  con- 
sideration of  them  needed.  Descriptions  of  many  tests  of  function  and  their 
interpretation  now  are  incorporated  in  the  chapters  in  Oxford  Medicine  on 
different  diseases.  Also  there  are  available  excellent  books  on  diagnosis  and 
diagnostic  technics  where  descriptions  of  tests  of  function  and  their  interpretation 
will  be  found.  The  reader,  seeking  information  about  different  tests  of  function, 
is  referred  to  other  chapters  in  Oxford  Medicine  and  to  the  books  just  cited. 
There  he  will  find  tests  of  the  function  of  almost  every  structure  in  the  body  de- 
scribed and  interpreted  with  advice  as  to  which  tests  to  use  and  when. 

It  has  seemed  worth  while,  however,  to  record  in  this  chapter  a  considerable 
number  of  the  normals  for  various  laboratory  tests,  many  of  which  are  needed  for 
an  appreciation  of  departures  from  noi-mal  encoimtered  and  noted  in  various 
places  in  the  chapters  in  Oxford  Medicine.    Such  a  table  follows. 


TABLE   OF   NORMAL   LABORATORY   V.ALUES  * 

Blood,  Plasma  or  Serum  Values 


Determination 

Material 
Analyzed 

Minimum 

Quantity 

Required 

cc. 

Normal 
Value 

Method 

Amino  acids 
(CO2     of     car- 
boxyl  carbon) 

Amylase 

Plasma 
Serum 

2 
2 

3.4-5.5  mg. 
per  100  cc. 

15-35  units 
per  100  cc. 

Hamilton  and  Van  Slyke :  /. 
Biol.  Client.  150:231,  1943. 

Adapted   from    Somogyi: 
Biol.  Clietn.  125:399,  1938. 

*  From  Case  Records  of  the  Massachusetts  General  Hospital,  New  England  Journal  of  Medi- 
cine, Vol.  234,  pages  24-28,  1946. 

Vol.  I.  1147 


TABLE  OF  NORMAL  LABORATORY  VALUES 


687 


Minimum 

Material 

Quantity 

Normal 

Determination 

Analyzed 

Required 
cc. 

Value 

Method 

Ascorbic  acid 

Plasma 

o-S 

0.4-1.0  mg. 

Butler,  Cushman  and  Mac- 

(vitamin  C) 

per  100  cc. 

(fasting) 

Lachlan :  /.  Biol.  Chem.  150: 
453,  1943- 

Ascorbic  acid 

White 

8 

25-40   mg.   per 

Ibid. 

cells 

(whole 
blood) 

100  cc. 

Bilirubin 

Serum 

2 

Direct,  0.4  mg. 

Malloy  and  Evelyn:  /.  Biol. 

(van  den 

per  100  cc; 

Chem.  119:481,  1937. 

Bergh  test) 

indirect 
(total)  0.7 
mg.  per  100 
cc. 

Calcium 

Serum 

2 

9.0-10.5  mg. 
per  100  cc. 

Fiske  and  Logan:  /.  Biol. 
Chem.  93:211,  1931;  Folin: 
Lab.  Manual  Biol.  Chem., 
5th  ed.,  p.  351. 

Carbon  dioxide 

Serum 

0.5 

26-28  meq. 

Van  Slyke  and  Neill:  /.  Biol. 

(content) 

per  liter 

C7/€w.  61:523,  1924;  Peters 
and  Van  Slyke :  Quant.  Clin. 
Chem.,  Vol.  II  (Methods), 
p.  283. 

Carotenoids: 

Serum 

1 

100-300  int. 

Josephs:  Bull.  Johns  Hopkins 

(total) 

units  per 
100  cc. 

Hasp.  65:112,  1939  (modi- 
fied for  photocolorimeter 
and  cahbrated  with  haliver 
oil  of  specified  vitamin  A 
content). 

Vitamin  A 

Serum 

2 

40-100  int. 
units  per 
100  cc. 

Chloride 

Serum 

0.5 

100-106  meq. 
per  liter 

Wilson  and  Ball:  /.  Biol. 
Chem.  79:221,  1928. 

Cholesterol 

Serum 

0-5 

150-230  mg. 
per  100  cc. 

Bloor:  J.  Biol.  Chem.  24:227, 
1916. 

Cholesterol 

Serum 

o-S 

65  per  cent  of 

Bloor  and  Knudson :  /.  Biol. 

esters 

total  choles- 
terol 

Chem.  27:107,  1916. 

Glucose 

Blood 

0.1 

70-100  mg. 
per  100  cc. 

(fasting) 

Folin :   Lab.  Manual  Biol. 
Cliem.,    sth    ed.,    p.    307; 
FoUn:    New  Eng.  J.  Med. 
206:727,  1932. 

Vol.  I.  1 147 


688 


TESTS  OF  FUNCTION  IN  INTERNAL  MEDICINE 


Determination 


Minimum 

Material 

QlTANTITY 

Normal 

Analyzed 

Required 
cc. 

Value 

Blood 

0.05 

14-16   gm.   per 
TOO  cc. 

Serum 

4 

4-8  microgm. 
per  100  cc. 

Serum 

2 

1-2  meq.  per 
liter 

Serum 

o-S 

15-35  mg. 
per  100  cc. 

Blood 

3 

19-22  vol. 
per  cent. 

Method 


Hemoglobin 

Iodine,  protein- 
bound  (thy- 
roid hormone) 

Magnesiimi 


Nonprotein 
nitrogen 

Oxygen: 
Capacity 


Arterial 
content 

Arterial  per- 
centage 
saturation 

Venous 
content 

Venous  per- 
centage 
saturation 

pH  (reaction) 


Phosphatase, 
acid 

Phosphatase, 
alkaline 


Blood 


Blood 


Serum 

Serum 
Serum 


0-5 


18-21  vol. 
per  cent. 

94-96  per  cent. 


10-16  vol. 
per  cent. 

60-85  per  cent. 


7-3S-7-4S 


0.5-2.0  units 
per  TOO  cc. 

2.0-4.5  units 
per  100  cc." 


Evelyn:  /.  Biol.  Chem.  115: 
63)  1936- 

Talbot,  Butler,  Saltzman  and 
Rodriguez:  J.  Biol.  Chem. 
153:479,  1944- 

Briggs:  /.  Biol.  Chem.  59:255, 
1924. 

Folin:  Lab.  Manual  Biol. 
Chem.,  5th  ed.,  p.  265. 

Van  Slyke  and  Neill:  /.  Biol. 
Chem.  61:523,  1924;  Peters 
and  Van  Slyke:  Quant. 
Clin.  Chem.,  Vol.  II  (Meth- 
ods), p.  321. 

Ibid. 


(Arterial  content  x  100)  -r- 
capacity. 

Ibid. 

(Venous  content  X  100)  -H 
capacity. 

Hastings  and  Sendroy:  /. 
Biol.  Chem.  61:695,  1924; 
Peters  and  Van  Slyke: 
Quant.  Clin.  Chem.,  Vol.  II 
(Methods),  p.  796. 

Gutman  and  Gutman:  /. 
Biol.  Chem.  136:201,  1940. 

Bodansky:  /.  Biol.  Chem. 
101:93,  1933  (using  the 
method  for  determining  in- 
organic phosphorus). 


*  In  the  newborn  infant  values  may  be  as  high  as  6  mg.  per  100  cc,  which  then  diminish 
during  the  first  year;  in  childhood  they  approach  the  normal  adult  average  value  of  3.5  mg. 

Vol.  I.  X147 


TABLE  OF  NORMAL  LABORATORY  VALUES 


Determination 


Minimum 
Material      Quantity  Normal 

Analyzed      Required  Value 


689 


Method 


Phosphorus, 
inorganic 


Potassium 


Protein : 
Total 


Serum 


Albumin 

GlobuKn 

Prothrombin 
clotting  time 

Pyruvic  acid 


Sodium 


Urea  nitrogen 


Uric  acid 


Serum 


Serum 


Serum 


Serum 


Plasma 


Blood 


Serum 


Serum 


3-4 


0.5  (macro) 
0.05  (micro) 


o-S 


0-5 


0-3 


0-5 


3.0-4.5  mg. 
per  100  cc." 


3.5-5.0  meq. 
per  liter 


6.5-8.0  gm. 
per  100  cc. 


Serum 


4-5-5-S  gm. 
per  100  cc. 

1.5-3.0  gm. 
per  100  cc. 

By  control 


0.7-1.2  mg. 
per  100  cc. 
(fasting) 

136-145  meq. 
per  Uter 

10-28  mg. 
per  100  cc. 


3-5  mg.  per 
100  cc. 


Fiske  and  Subbarow:  J .  Biol. 
Cliem.  66^375,  1925;  FoUn: 
Lab.  Manual  Biol.  Chem., 
5th  ed.,  p.  341  (modified 
for  photocolorimeter). 

Fiske  and  Litarczek  in  Folin: 
Lab.  Manual  Biol.  Chem., 
5th  ed.,  p.  353. 

Macro:  Peters  and  Van  Slyke: 
Quant.  Clin.  Chem.,  Vol.  II 
(Methods),  p.  691. 

Micro;  Lowry  and  Hastings: 
/.  Biol.  Chevi.  143:257, 
1942. 

Ibid. 


Ibid. 

Quick:  J.  A.  M.  A.  110:1658, 
1938. 

Friedemann  and  Haugen:/. 
Biol.  Chem.  147:415,  1943; 
Bueding  and  Wortis.  Ibid. 
133:585,  1940- 

Butler  and  Tuthill:  J.  Biol. 
Chem.  gy.i-ji,  1931. 

Van  Slyke:  /.  Biol.  Chem. 
73:695,  1927;  Peters  and 
Van  Slyke:  Qtmnt.  Clin. 
Chem.,  Vol.  II  (Methods), 
P-  372. 

Fohn:/.  Biol.  Chem.  101:111, 
1933- 


*  The  value  parallels  the  rate  of  growth,  diminishing  from  approximately  14  units  per  100  cc. 
in  infancy  to  5  units  in  adolescence  and  thereafter  being  maintained  at  approximately  3.5  units. 
Vol.  I.  1 147 


690        TESTS  OF  FUNCTION  IN  INTERNAL  MEDICINE 


•  Urine  Values 


Minimum 

Determination 

Quantity 

Required 

cc. 

Normal  Value 

Method 

Albumin    (quantita- 

10 

0 

Folin:  Lab.  Manual  Biol.  Chem., 

,     tive) 

5th  ed.,  p.  225. 

Creatine 

24-hour 

Less  than  100  mg.  per 

Folin:  Lab.  Manual  Biol.  Chem., 

sample 

24  hr.* 

Sth  ed.,  p.  163. 

Creatinine 

24-hour 

15-25  mg.  per  kg.f 

Ibid.,  p.  159  (modified  for  photo- 

sample 

colorimeter). 

Diastase 

2 

Dilution  of  1:4  to 

Stitt:    Pracl.     Bad.    Ham.     &• 

1:16 

Parasitol.,  9th  ed.,  p.  731. 

Follicle  stimulating 

24-hour 

Before    puberty,    less 

Klinefelter,   Albright  and   Gris- 

hormone 

sample 

than  6.5  mouse 

wold:     /.     Clin.     Endocrinol. 

units    per    24    hr.; 

3:529,  1943. 

after    puberty    6.5- 

52  mouse  units  per 

24  hr.;  after  meno- 

pause 104-600 

mouse      units      per 

24  hr. 

Sugar: 

Total      (quantita- 

5 

0 

Benedict:  /.  A.  M.  A.  57:1193, 

tive) 

1911. 

Total  (roughly 

o.S 

0 

Somogyi:    /.    Lab.    Clin.    Med. 

quantitative) 
Fermentable 


Fructose 

Galactose   or   lac- 
tose 


26:1220,  1941. 

Hawk  and  Bergheim:  Pra^t. 
Physiol.  Chem.,  loth  ed.,  p. 
750. 

Ibid.,  p.  772. 

(Total  sugar  X  1.24)  minus  fer- 
mentable sugar. 


*  Per  kilogram  of  body  weight,  the  excretion  is  higher  in  women  and  children  than  in  men, 
and  still  higher  in  infants. 

t  The  value  depends  on  the  ratio  of  muscle  to  fat  in  the  body  mass  of  the  patient.  The  higher 
the  ratio,  the  greater  the  creatinine  excretion  per  kilogram  of  total  body  weight.  Because  this 
ratio  is  low  in  infants,  the  excretion  per  kilogram  is  low. 

Vol.  1.  1 147 


TABLE  OF  NORMAL  LABORATORY  VALUES 


691 


Determination 


Minimum 
Quantity 
Required 

CO. 


Normal  Value 


Method 


Osazone,   differen- 
tiation of 

Urobilinogen 
1 7-ketosteroids 


12-hour 


Dilution  of  i  :4  to  i  -.^o 


Ibid.,  p.  50. 

Wallace  and  Diamond:  Arch.  Int. 
Med.  35:698,  1925. 

Under  8  yr.,  0-2  mg.  Talbot,  Butler,  MacLachlan  and 
per  24  hr.;  adoles- 
cents, 2-20  mg.  per 
24  hr.;  males,  8-20 
mg.  per  24  hr.;  fe- 
males, 5-14  mg.  per 
24  hr. 


Jones:  J .  Biol.  Cliem.  136:365, 
1940;  Fraser,  Forbes,  Albright, 
Sulkowitch  and  Reifenstein: 
J.  Clin.  Endocrinol.  1:234, 
1941. 


Liver  Function  Tests 


Minimum 

Amount 

Material 

Quantity 

Normal 

Determination 

Administered 

Analyzed 

Required 
cc. 

Value 

Method 

Bromsulfalein 

2  mg.  per  kg. 

Serum 

2 

Less  than 

Rosenthal  and 

intravenously 

(30  min. 

5  per 

White:  /.  A.  M. 

after  in- 

cent, re- 

A. 84:1112,  1925; 

jection) 

tention 

Peters  and  Van 
Slyke:  Quant. 
Clin.  Cltem.,  Vol. 
II  (Methods), 
p.  910. 

Bromsulfalein  * 

5  mg.  per  kg. 

Serum 

2 

Less   than 

Ibid,  (modified, 

intravenously 

(45  min. 
after  in- 
jection) 

5  per 
cent,  re- 
tention 

i.e.,  result -^  2.5) 

Cephalin 

0 

Serum 

0.2 

Up  to 

Hanger:    /.     Clin. 

flocculation 

+  +    in 
48  hr. 

Investigation 
18:261,  1939. 

Galactose 

0.5  gm.  per  kg. 

Blood 

I 

Less   than 

Basset,  Althausen 

tolerance 

intravenously 

5  mg.  at 
75  min. 

and  Coltrin:  Am. 
J.  Digest.  Dis.  dr 
Nutrition    8:432, 
1941. 

*  The  2-mg.  method  is  used  in  patients  with  shght  jaundice,  and  the  5-mg.  method  in  patients 
without  jaundice;   the  method  is  valueless  in  patients  with  obvious  jaundice. 

Vol.  I.  1 147 


692        TESTS  OF  FUNCTION  IN  INTERNAL  MEDICINE 


Minimum 

Determination 

Amount 
Administered 

Material 
Analyzed 

Quantity 

Required 

cc. 

Normal 
Value 

Method 

Hippuric  acid 

1.77    gm.  sodi- 

Urine 

i-hr. 

Greater 

Quick,     Ottenstein 

um  benzoate 

sample 

than  I 

and  Weltchek: 

intraven- 

gm. 

Proc.  Soc. 

ously 

Exper.    Biol,    cf 
Med.  38:77, 
1938;  Moser, 
Rosenak  and 
Hasterlik:  Am. 
J.  Digest.  Dis.  b° 
Nutrition  9:183, 
1942. 

Renal  Function  Tests 


Determination 


Minimum 
Amount  Material     Quantity       Normal 

Administered      Analyzed     Required        Value 


Method 


Phenolsulfon- 
phthalein 


I  cc. 
intravenously 


Urine 


Total 


Urea  clearance 


Blood  and 
urine 


output 


Blood,  I 
cc; 
urine, 
two 
i-hr. 
samples 


25  per 
cent,  or 
more  in 
first 

15  min.; 
40  per 
cent,  or 
more  in 
30  min.; 
55  per 
cent,  or 
more  in 
2  hr. 

75  to  125 
per  cent, 
of  nor- 
mal 


Chapman:  New 
Eng.  J.  Med. 
214:16,  1936. 


Peters  and 
Van  Slyke: 
Quant.  Clin. 
Chem.,  Vol.  H 
(Methods), 
p.  564. 


Vol.  I.  1 147 


TABLE  OF  NORMAL  LABORATORY  VALUES 


693 


Hematologic  Values 


Determination 


Minimum 
Quantity 
Require 


Normal  Value 


Method 


Bleeding  time 


Clotting  time 

Sedimentation  rate 
(two  methods) 


Hematocrit  reading 
(percentage  volume 
of  packed  red  cells) 

Hemoglobin 

Mean  corpuscular 
volume 

Mean  corpuscular 
hemoglobin 

Mean  corpuscular 
hemoglobin  con- 
centration 


0.05 


Below  4^  min. 


Below  20  min. 

Less    than   0.35    mm. 
per  min. 

Less     than     15     mm. 
per  hr. 

Male,  40-54  per 
cent;  female, 
37-47  per  cent. 

14-16  gm.  per 
100  cc. 

80-94  cu.  microns 
27-32  micromicrogm. 
33-38  per  cent. 


Lee  and  White  in  Todd  and 
Sanford:  Clin.  Diag.  by  Lab. 
Methods,  loth  ed.,  p.  199. 

Duke:  /.  A.  M.  A.  55:1185, 
1910. 

Rourke  and  Ernstene:  /.  Clin. 
Investigation  8:545,  1930. 

Modification*  of  Wintrobe  and 
Landsberg:  Am.  J.  M.  Sc. 
189:102,  1935. 

lUd. 


Evelyn:  /.  Biol.  Chem.  115:63, 
1936. 

(Hematocrit  X  10)  -v-  red     cells 
(in  millions). 

(Gm.     of     hemoglobin  X  10)  4- 
red  cells  (in  millions) 

(Gm.    of   hemoglobin  X  100)  -r- 
hematocrit. 


*  Internal  diameter  of  tube  should  be  4  mm.  instead  of  2.5  mm. 


Spinal  Fluid  Values 


Determination 


Minimum 

Quantity 

Reqltired 

cc. 


Normal  Value 


Method 


Initial  pressure 
Cell  count 


70-180  mm.  of  water 

0-5  mononuclear 
cells  (lympho- 
cytes) 


Vol.  I.  1147 


694        TESTS  OF  FUNCTION  IN  INTERNAL  MEDICINE 


Minimum 


Determination         ^^  ^  Normal  Value 

Required 


Method 


Chloride 
Protein 

Glucose 
Colloidal  gold 


120-130  meq.  per 
liter 


Wilson  and  Ball:  /.  Biol.  Chem. 
79:221,  1928. 

0.6  15-45  mg.  per  100  cc.       Ayer,     Dailey     and     Fremont- 

Smith:  Arch.  Neurol.  6°  Psy- 
chiat.  26:1038,  193 1. 

I  50-75  mg.  per  100  cc.       Same    as    that    for    blood    (see 

above) . 

0.1  coooooooco  Wuth  and  Faupel;  Bull.  Johns 

Hopkins  Hosp.  40:297,   1927. 


Miscellaneous  Values 


Determination 


Minimum 
Material      Quantity  Normal 

Analyzed      Required  Value 


Method 


Stool  fat 


Calculi 


Congo  red  test 


Serum 


Repre- 
senta- 
tive 
sample 

Repre- 
senta- 
tive 
sample 


Less  than  30 
per  cent,  dry 
wt. 


More  than  60 
per  cent,  reten- 
tion in  serum 
after  i  hr. 


Tidwell  and  Holt:  /.   Biol. 
Chem.  112:605,  1936. 


Mcintosh  and  Salter:  J.  Clin. 
Investigation  21:751,  1942. 


Bennhold:  Deutsches  Arch.  f. 
klin.  Med.  142:32,  1923. 


September  i,  1947. 


Vol.  I.  1147 


CHAPTER  XVII 
THE  TREATMENT  OF  DISEASE 

By  sir  WILLIAM  OSLER 


As  true  today  as  when  Celsus  made  the  remark,  "  The  dominant 
view  of  the  nature  of  disease  controls  its  treatment."  As  is  our  pathol- 
ogy so  is  our  practice;  what  the  pathologist  thinks  today  the  physician 
does  tomorrow.  Roughly  grouped,  there  have  been  three  great  concep- 
tions of  the  nature  and  treatment  of  disease. 

A.  For  long  centuries  it  was  believed  to  be  the  direct  outcome  of 
sin,  "  flagellum  Dei  pro  peccatis  mundi,"  to  use  Cotton  Mather's  phrase, 
and  the  treatment  was  simple — a  readjustment  in  some  way  of  man's 
relation  with  the  invisible  powers,  malign  or  benign,  which  had  inflicted 
the  scourge.  From  the  thrall  of  this  "  sin  and  sickness  "  view  man 
has  escaped  so  far  as  no  longer,  at  least  in  Anglo-Saxon  communities, 
to  have  a  proper  saint  for  each  infirmity.  Against  this  strong  bias 
towards  the  supernatural  even  the  wisdom  of  Solomon  could  not  pre- 
vail; was  not  the  great  book  of  his  writings  which  contained  medicine 
for  all  manner  of  diseases  and  lay  open  for  the  people  to  read  as  they 
came  into  the  temple  removed  by  Hezekiah  lest  out  of  confidence  in 
remedies  they  should  neglect  their  duty  in  calling  and  relying  upon 
God?  And  the  modern  book  of  reason,  which  lies  open  to  all,  is  read 
only  by  a  few  in  the  more  civilized  countries.  The  vast  majority  are 
happy  in  the  childlike  faith  of  the  childhood  of  the  world.  I  am  told 
that  annually  more  people  seek  help  at  the  shrine  of  St.  Anne  de 
Beaupre,  in  the  Province  of  Quebec,  than  at  all  the  hospitals  of  the 
Dominion  of  Canada.  How  touching  at  Rome  to  see  the  simple  trust 
of  the  poor  in  some  popular  Madonna,  such  as  the  Madonna  del  Parto! 
It  lends  a  glow  to  the  cold  and  repellent  formalism  of  the  churches. 
In  all  matters  relating  to  disease  credulity  remains  a  permanent  fact, 
uninfluenced  by  civilization  or  education. 

B.  From  Hippocrates  to  Hunter  the  treatment  of  disease  was  one 
long  traffic  in  hypotheses;  variants  at  different  periods  of  the  doctrine 
of  the  four  humors,  as  dominated  by  some  strong  mind  in  active  revolt 

695 


696  THE  TREATMENT  OF  DISEASE 

it  would  undergo  temporary  alteration.  The  peccant  humors  were  re- 
moved by  purging,  bleeding,  or  sweating,  and  until  the  early  years  of 
the  nineteenth  century  there  was  very  little  change  in  the  details.  To 
a  very  definite  but  entirely  erroneous  pathology  was  added  a  treatment 
most  rational  in  every  respect,  had  the  pathology  been  correct!  The 
practice  of  the  early  part  of  the  last  century  differed  very  little  from 
that  which  prevailed  in  the  days  of  Sydenham,  except,  perhaps,  that  our 
grandfathers  were,  if  possible,  more  ardent  believers  in  the  lancet. 

C.  In  the  past  fifty  years  our  conception  of  the  nature  of  disease 
has  been  revolutionized,  and  with  a  recognition  that  its  ultimate  pro- 
cesses, whether  produced  by  external  agents  or  the  result  of  modifications 
in  the  normal  metabolism,  are  chemico-physical,  we  have  reached  a 
standpoint  from  which  to  approach  the  problems  of  prevention  and  cure 
in  a  rational  way.  Let  me  indicate  briefly  the  directions  in  which  the 
new  science  has  transformed  the  old  art. 

In  the  first  place,  the  discovery  of  the  cause  of  many  of  the  great 
scourges  has  changed  not  only  its  whole  aspect,  but,  indeed,  we  may 
say,  the  very  outlook  of  humanity.  No  longer  is  our  highest  aim  to 
cure,  but  to  prevent  disease;  and  in  its  career  of  usefulness  the  profes- 
sion has  never  before  had  a  triumph  such  as  we  have  witnessed  in  the 
abolition  of  many  fearful  scourges.  Great  as  have  been  the  Listerian 
victories  in  surgery,  they  are  but  guerrilla  skirmishes,  so  to  speak,  in 
comparison  with  the  Napoleonic  campaigns  which  medicine  is  waging 
against  the  acute  infections.  These  are  glorious  days  for  the  race. 
Nothing  has  been  seen  like  it  on  this  old  earth  since  the  destroying  angel 
stayed  his  hand  on  the  threshing-floor  of  Araunah  the  Jebusite.  For 
seventeen  years  Cuba,  once  a  pest-house  of  the  tropics,  has  been  free 
from  a  scourge  which  has  left  an  indelible  mark  in  the  history  of  the 
Englishman,  Spaniard,  and  American  of  the  New  World.  Today  the 
Canal  Zone  of  Panama,  for  years  the  graveyard  of  the  white  man,  has 
a  death  rate  as  low  as  that  in  any  city  of  the  United  States.  In  the 
island  of  Porto  Rico,  where  many  thousands  have  died  annually  of 
tropical  anemia,  the  death  rate  has  been  cut  in  half  by  the  work  of  Ash- 
ford  and  others.  But,  above  all,  the  problem  of  life  in  the  tropics  for 
the  white  man  has  been  solved,  since  malaria  may  now  be  prevented  by 
very  simple  measures.  These  are  some  of  the  recent  results  of  lal:)ora- 
tory  studies  which  have  placed  in  our  hands  a  power  for  good  never 
before  wielded  by  man. 

Secondly,  a  fuller  knowledge  of  etiology  has  led  to  a  return  to 
methods  which  have  for  their  object,  not  so  much  the  combating  of  the 
disease  germ  or  of  its  products,  as  the  rendering  of  conditions  in  the 
body  unfavorable  for  its  propagation  and  action.    How  fruitful  in  prac- 


THE  TREATMENT  OF  DISEASE  697 

tical  results,  for  example,  have  been  the  new  views  on  tuberculosis !  Not 
that  the  discovery  of  the  bacillus  itself  modified  immediately  our  treat- 
ment of  the  disease,  but,  as  so  often  happens,  a  combination  of  circum- 
stances was  responsible  for  the  happy  revolution — the  recognition  of  the 
widespread  prevalence  of  the  infection,  the  great  frequency  with  which 
healed  lesions  were  found,  and  the  knowledge  of  the  importance  of 
the  character  of  the  tissue  soil,  led  to  the  substitution  of  the  open-air 
and  dietetic  treatment  for  the  nauseous  mixtures  with  which  our  patients 
were  formerly  drenched.  We  scarcely  appreciate  the  radical  change 
which  has  occurred  in  our  views  even  within  a  few  years.  Contrast 
with  a  recent  work  on  tuberculosis  one  published  thirty-five  or  forty 
years  ago.  In  the  latter  the  drug  treatment  takes  up  the  larger  share, 
while  in  the  former  it  is  reduced  to  a  page  or  two.  And  it  is  not  only 
in  the  acute  infections  that  the  use  of  the  "  non-naturals,"  as  the  old 
writers  called  them,  has  replaced  other  forms  of  treatment,  but  in  diet, 
exercise,  massage,  and  hydrotherapy,  we  are  every  day  finding  out  the 
enormous  importance  of  measures  which  too  often  have  been  used  with 
greatest  skill  by  those  outside  or  on  the  edge  of  the  profession. 

Thirdly,  the  study  of  morbid  anatomy  combined  with  careful  clinical 
observations  has  taught  us  to  recognize  our  limitations,  and  to  accept 
the  fact  that  a  disease  itself  may  be  incurable,  and  that  the  best  we  can 
do  is  to  relieve  symptoms  and  to  make  the  patient  comfortable.  The 
relation  of  the  profession  to  this  group,  particularly  to  certain  chronic 
maladies  of  the  nervous  system,  is  a  very  delicate  one.  It  is  a  hard  mat- 
ter, and  really  not  often  necessary  (since  Nature  usually  does  it  quietly 
and  in  good  time),  to  tell  a  patient  that  he  is  past  all  hope.  As  Sir 
Thomas  Browne  says,  "  It  is  the  hardest  stone  you  can  throw  at  a  man 
to  tell  him  that  he  is  at  the  end  of  his  tether,"  and  yet,  put  in  the  right 
way  to  an  intelligent  man  it  is  not  always  cruel.  Let  us  remember  that 
we  are  the  teachers,  not  the  servants,  of  our  patients,  and  we  should 
be  ready  to  make  personal  sacrifices  in  the  cause  of  truth,  and  of  loyalty 
to  the  profession.  Our  inconsistent  attitude  is,  as  a  rule,  the  outcome 
of  the  circumstances  that  of  the  three  factors  in  practice,  heart,  head 
and  pocket,  to  our  credit,  be  it  said,  the  first  named  is  most  potent.  How 
often  does  the  consultant  find  the  attending  physician  resentful  or  ag- 
grieved when  told  the  honest  truth  that  there  is  nothing  further  to  be 
done  for  the  cure  of  his  patient!  To  accept  a  great  group  of  maladies, 
against  which  we  have  never  had  and  can  scarcely  ever  hope  to  have 
curative  measures,  makes  some  men  as  sensitive  as  though  we  were  our- 
selves responsible  for  their  existence.  These  very  cases  are  "  rocks  of 
offense  "  to  many  good  fellows  whose  moral  decline  dates  from  the  rash 
promise  to  cure.     We  work  by  wit  and  not  by  witchcraft,  and  while 


698  THE  TREATMENT  OF  DISEASE 

these  patients  have  our  tenderest  care,  and  we  must  do  what  is  best 
for  the  relief  of  their  sufferings,  we  should  not  bring  the  art  of  medicine 
into  disrepute  by  quack-like  promises  to  heal,  or  by  wire-drawn  attempts 
to  cure  in  what  old  Burton  calls  "  continuate  and  inexorable  maladies." 

Fourthly,  the  new  studies  on  the  functions  of  organs  and  their  per- 
versions have  led  to  most  astonishing  results  in  the  use  of  the  products 
of  metabolism,  which  time  out  of  mind  physicians  have  employed  as 
medicines.  Pliny's  "Natural  History"  (Bohn,  London,  1855-57,  vol. 
ii,  291)  is  a  storehouse  of  information  on  the  medicinal  use  of  parts 
of  animals  or  of  various  secretions  and  excretions.  Much  of  the  hum- 
buggery  and  quackery  inside  and  outside  of  the  profession  has  been 
concerned  with  the  use  of  the  most  unsavory  of  these  materials.  The 
seventeenth  century  pharmacopeias  were  full  of  them,  and  in  his  oration 
at  the  Hunterian  Society,  1902,  Dr.  Arthur  T.  Davies  has  given  an 
interesting  historical  sketch  of  their  use  in  practice.  Modern  metabolic 
therapy  represents  one  of  the  greatest  triumphs  of  science.  The  demon- 
stration of  insufficiency  of  the  thyroid  gland  is  a  brilliant  example  of 
successful  experimental  inquiry,  and  as  time  has  passed  the  good  re- 
sults of  treatment  in  suitable  cases  have  become  more  and  more  evident. 
Before  long,  no  doubt,  we  shall  be  able  to  meet,  in  the  same  happy 
way,  the  perverted  functions  which  lead  to  such  diseases  as  exophthal- 
mic goitre,  Addison's  disease,  and  acromegaly;  and  as  our  knowledge 
of  the  pancreatic  function  and  carbohydrate  metabolism  becomes  more 
accurate  we  shall  probably  be  able  to  place  the  treatment  of  diabetes  on 
a  sure  foundation.  And  it  is  not  only  on  the  organic  side  that  progress 
has  been  made.  Important  discoveries  relating  to  the  metabolism  of  the 
inorganic  constituents,  such  as  those  relative  to  acidosis,  have  opened 
a  new  and  most  hopeful  chapter  in  scientific  medicine. 

But  the  best  of  human  effort  is  flecked  and  stained  with  weakness, 
and  even  the  casual  observer  may  note  dark  shadows  in  the  bright  pic- 
ture. Organotherapy  illustrates  at  once  one  of  the  great  triumphs  of 
science  and  the  very  apotheosis  of  charlatanry.  One  is  almost  ashamed 
to  speak  in  the  same  breath  of  the  credulousness  and  cupidity  by  which 
even  the  strong  in  intellect  and  the  rich  in  experience  have  been  carried 
off  in  a  flood  of  pseudo-science.  This  has  ever  been  a  difficulty  in  the 
profession.  The  art  is  very  apt  to  outrun  or  override  the  science, 
and  play  the  master  where  the  true  role  is  that  of  the  servant. 

And,  lastly,  we  have  advanced  firmly  along  a  new  road  in  the  treat- 
ment of  diseases  due  to  specific  microorganisms,  with  the  toxic  products 
of  which  we  are  learning  to  cope  successfully.  The  treatment  with 
antitoxins  and  bacterial  vaccines,  so  successfully  started,  bears  out  the 
truth  of  that  keen  comment  of  Celsus:     "He  will  treat  the  disease 


THE  TREATMENT  OF  DISEASE  699 

properly  whom  the  first  origin  of  the  cause  has  not  deceived."  We  are 
still  far  from  the  goal  in  some  of  the  most  important  and  fatal  infec- 
tions, but  anyone  acquainted  in  even  slight  measure  with  the  progress 
of  the  past  twenty  years  cannot  but  have  confidence  in  the  future.  Con- 
sidering that  the  generation  is  still  active  which  opened  the  whole  ques- 
tion, we  cannot  but  feel  hopeful  in  spite  of  disappointments  here  and 
failures  there.  But  in  our  pride  of  progress  let  us  remember  cancer  and 
pneumonia.  The  history  of  the  latter  disease  affords  a  good  illustration 
of  the  truth  of  the  remark  of  Celsus  with  which  I  began.  Year  by  year 
the  lesson  of  pneumonia  is  a  lesson  of  humility.  For  purposes  of  com- 
parison statistics  are  not  available,  but  it  is  not  likely  that  the  great 
masters  from  Galen  to  Grisolle  lost  a  larger  number  of  cases  than  we 
do.  Pneumonia  has  always  been,  as  today,  a  dreaded  and  a  fatal  dis- 
ease. For  one  thing  let  us  be  thankful.  We  have  had  the  courage  to 
abandon  the  expectorant  mixtures,  the  depressants,  the  cardiac  sedatives, 
the  blisters,  the  emetics,  the  resulsives,  the  purges,  the  poultices,  and,  to 
a  great  extent,  the  bleedings.  Surely  our  forefathers  must  have  killed 
some  patients  by  the  appalling  ferocity  of  their  treatment,  or  to  have 
stood  it  the  constitutions  of  those  days  must  have  been  more  robust. 
We  still  await,  but  await  in  hope,  the  work  that  will  remove  the  reproach 
of  the  mortality  bills  in  this  disease.  I  say  reproach  because  we  really 
feel  it,  and  yet  act  justly,  for  who  made  us  responsible  for  its  benign  or 
malignant  nature?  We  can  relieve  symptoms,  but  we  must  find  the 
means  which  will,  on  the  one  hand,  limit  the  extension  of  the  process, 
loosen  the  exudate,  minimize  the  fluxion,  control  the  alveolar  diapedesis, 
and,  on  the  other  hand,  diminish  the  output  of  the  toxins,  neutralize  those 
in  circulation,  or  strengthen  the  opsonic  power  of  the  blood.  But  some- 
one will  say,  Is  this  all  your  science  has  to  tell  us?  Is  this  the  outcome 
of  decades  of  good  clinical  work,  of  patient  study  of  the  disease,  of 
anxious  trial  in  such  good  faith  of  so  many  drugs?  Give  us  back  the 
childlike  trust  of  the  fathers  in  antimony  and  in  the  lancet  rather  than 
this  cold  nihilism.  Not  at  all !  Let  us  accept  the  truth,  however  unpleas- 
ant it  may  be,  and  with  the  death  rate  staring  us  in  the  face,  let  us  not 
be  deceived  with  vain  fancies.  Not  alone  in  pneumonia,  but  in  the 
treatment  of  certain  other  diseases,  do  we  need  a  stern,  iconoclastic 
spirit  which  leads,  not  to  nihilism,  but  to  an  active  skepticism, — not  the 
passive  skepticism  born  of  despair,  but  the  active  skepticism  born  of  a 
knowledge  that  recognizes  its  limitations  and  knows  full  well  that  only 
in  this  attitude  of  mind  can  true  progress  be  made.  I  hope  to  live  to 
see  a  true  treatment  of  pneumonia.  Before  long  we  should  be  able  to 
cope  with  the  products  of  the  pneumococci;  it  may  indeed  come  within 
the  list  of  preventable  diseases. 


700  THE  TREATMENT  OF  DISEASE 

II 

Along  these  five  lines  the  modern  conception  of  the  nature  of  disease 
has  radically  altered  our  practice.  The  personal  interest  which  we  take 
in  our  fellow  creatures  is  apt  to  breed  a  sense  of  superiority  to  their 
failings,  and  we  are  ready  to  forget  that  we  ourselves,  singularly  human, 
illustrate  many  of  the  common  weaknesses  which  we  condemn  in  them. 
In  no  way  is  this  more  striking  than  in  the  careless  credulity  we  display 
in  some  matters  relating  to  the  treatment  of  disease.  Recently  the 
Times  had  an  editorial  upon  a  remark  of  Bernard  Shaw  that  the  cleverest 
man  will  believe  anything  he  wishes  to  believe,  in  spite  of  all  the  facts 
and  textbooks  in  the  world.  We  are  at  the  mercy  of  our  wills  much 
more  than  of  our  reason  in  the  formation  of  our  beliefs,  which  we  adopt 
in  a  lazy,  haphazard  way,  without  taking  much  trouble  to  inquire  into 
their  foundation.  But  I  am  not  going  to  discuss,  were  I  able,  this 
Shavian  philosophy ;  but  it  will  serve  as  an  introduction  to  a  few  remarks 
on  the  Nemesis  of  Faith  which  in  all  ages  readily  overtakes  doctors  and 
the  public  alike.  Without  trust,  without  confidence,  without  faith  in 
himself,  in  his  tools,  in  his  fellowmen,  no  man  works  successfully  or 
happily.  For  us,  however,  it  must  never  be  the  blind  unquestioning  trust 
of  the  devotee,  but  the  confidence  of  the  inquiring  spirit  that  would  prove 
all  things.  But  it  is  so  much  easier  to  believe  than  to  doubt,  for  doubt 
connotes  thinking  and  the  expenditure  of  energy,  and  often  the  disrup- 
tion of  the  status  quo.  And  then  we  doctors  have  always  been  a  simple, 
trusting  folk!  Did  we  not  believe  Galen  implicitly  for  1,500  years  and 
Hippocrates  for  more  than  2,000?  In  the  matter  of  treatment  the  placid 
faith  of  the  simple  believer,  not  the  fighting  faith  of  the  aggressive 
doubter,  has  ever  been  our  besetting  sin. 

In  the  progress  of  knowledge  each  generation  has  a  double  labor — 
to  escape  from  the  intellectual  thralls  of  the  one  from  which  it  has 
emerged  and  to  forge  anew  its  own  fetters.  Upon  us  whose  work  lay 
in  the  last  quarter  of  the  nineteenth  century  fell  the  great  struggle  with 
that  many-headed  monster,  Polypharmacy — not  the  true  polypharmacy 
which  is  the  skillful  combination  of  remedies,  but  the  giving  of  many — 
the  practice  of  at  once  discharging  a  heavily  loaded  prescription  at  every 
malady,  or  at  every  symptom  of  it.  Much  has  been  done  and  an  extraor- 
dinary change  has  come  over  the  profession,  but  it  has  not  been  a  fight 
to  the  finish.  Many  were  lukewarm ;  others  found  it  difificult  to  speak 
without  giving  offense  in  quarters  where  on  other  grounds  respect  and 
esteem  were  due.  As  an  enemy  to  indiscriminate  drugging,  I  have  often 
been  branded  as  a  therapeutic  nihilist.  That  I  should  even  venture  to 
speak  on  the  subject  calls  to  mind  what  Professor  Peabody  of  Harvard 


THE  TREATMENT  OF  DISEASE  701 

remarked  about  Jacob  Bigelow,  that,  "  for  his  professorship  of  Materia 
Medica  he  had  very  much  the  same  quahfications  that  a  learned  unbe- 
Hever  might  have  for  a  professorship  of  Christian  theology.  No  other 
man  of  his  time  had  so  little  faith  in  drugs."  I  bore  this  reproach 
cheerfully,  coming,  as  I  knew  it  did,  from  men  who  did  not  appreciate 
the  difference  between  the  giving  of  medicines  and  the  treatment  of  dis- 
ease; moreover  it  was  for  the  galled  jade  to  wince,  my  withers  were 
unwrung.  The  heavy  hands  of  the  great  Arabians  grow  lighter  in  each 
generation.  Though  dead,  Rhazes  and  Avicenna  still  speak,  not  only  in 
the  Arabic  signs  which  we  use,  but  in  the  combinations  and  multiplicity 
of  the  constituents  of  too  many  of  our  prescriptions.  We  are  fortu- 
nately getting  rid  of  routine  practice  in  the  use  of  drugs.  How  many 
of  us  now  prescribe  an  emetic?  And  yet  that  shrewd  old  man,  Nathanial 
Chapman,  who  graced  the  profession  of  Philadelphia  for  so  long,  used 
to  say,  "  Everything  else  I  have  written  may  disappear,  but  my  chapter 
on  emetics  will  last !  "  How  much  less  now  does  habit  control  our  prac- 
tice in  the  use  of  expectorants?  The  blind  faith  which  some  men  have 
in  medicines  illustrates  too  often  the  greatest  of  all  human  capacities — 
the  capacity  for  self-deception.  One  special  advantage  of  the  skeptical 
attitude  of  mind  is  that  a  man  is  never  vexed  to  find  that  after  all  he 
has  been  in  the  wrong.  It  is  an  old  story  that  a  man  may  practice  medi- 
cine successfully  with  a  very  few  drugs.  Locke  had  noticed  this,  proba- 
bly in  the  hands  of  his  friend  Sydenham,  since  he  says,  "  You  cannot 
imagine  how  far  a  little  observation  carefully  made  by  a  man  not  tied 
up  to  the  four  humors  .  .  .  would  carry  a  man  in  the  curing  of  dis- 
eases, though  very  stubborn  and  dangerous,  and  that  with  very  little 
and  common  things  and  almost  no  medicine  at  all."  Boerhaave  com- 
mented upon  this  truth  in  a  remark  of  Sydenham  "  that  a  person  well 
skilled  in  cases  seldom  needs  remedies."  The  study  of  the  action  of 
drugs,  always  beset  with  difficulties,  is  rapidly  passing  from  the  empiri- 
cal stage,  and  this  generation  may  expect  to  see  the  results  of  studies 
which  have  already  been  most  promising.  It  is  very  important  that  our 
young  men  should  get  oriented  early  in  this  matter  of  drug  treatment. 
Our  teachers  used  to  send  us  to  the  works  of  John  Forbes  ("  Nature 
and  Art  in  the  Cure  of  Disease,"  J.  Churchill,  London,  1857),  and  to 
Jacob  Bigelow  ("  Nature  in  Disease,"  Ticknor  and  Fields,  Boston, 
1854),  for  clear  views  of  the  subject.  A  book  has  been  written  by  Dr. 
Harrington  Sainsbury,  the  well-known  London  physician  and  teacher 
("  Principia  Therapeutica,"  E.  P.  Dutton  &  Company,  New  York, 
1907),  which  deals  with  these  problems  in  the  same  philosophic  manner. 
It  opens  with  a  delightful  dialogue  between  the  pathologist  and  the 
physician.     He  lays  his  finger  on  the  weak  point  of  the  pure  morbid 


702  THE  TREATMENT  OF  DISEASE 

anatomist  who  thinks  of  the  lesion  only,  and  not  enough  of  the  func- 
tion which  even  a  seriously  damaged  organ  may  be  able  to  carry  on. 
The  book  should  be  in  the  hands  of  every  practitioner  and  senior  student. 
Some  of  you  may  have  heard  of  the  lecture-room  motto  of  that  distin- 
guished pathologist  and  surgeon,  and  the  first  systematic  writer  on 
morbid  anatomy  in  the  United  States,  S.  D.  Gross :  "  Principles, 
gentlemen,  principles!  principles!!"  And  it  is  upon  these  fundamental 
aspects  that  Dr.  Sainsbury  dwells  in  his  most  suggestive  work,  which 
I  would  like  to  see  adopted  as  a  textbook  in  every  medical  school  in  the 
land. 

And  we  are  yet  far  too  credulous  and  supine  in  another  very  im- 
portant matter.  Each  generation  has  its  therapeutic  vagaries,  the  out- 
come, as  a  rule,  of  attempts  to  put  prematurely  into  practice  theoretical 
conceptions  of  disease.  As  members  of  a  free  profession  we  are  ex- 
pected to  do  our  own  thinking;  and  yet  the  literature  that  comes  to  us 
daily  indicates  a  thraldom  not  less  dangerous  than  the  polypharmacy 
from  which  we  are  escaping.  I  allude  to  the  specious  and  seductive 
pamphlets  and  reports  sent  out  by  the  pharmaceutical  houses,  large  and 
small.  We  owe  a  deep  debt  to  the  modern  manufacturing  pharmacist, 
who  has  given  us  pleasant  and  potent  medicines  in  the  place  of  the 
nauseous  and  weak  mixtures;  and  such  firms  as  Parke,  Davis  &  Com- 
pany, of  the  United  States,  and  Burroughs  &  Wellcome,  of  England, 
have  been  pioneers  in  the  science  of  pharmacology.  But  even  the  best 
are  not  guiltless  of  exploiting  in  the  profession  the  products  of  a  pseudo- 
science.  Let  me  specify  three  items  in  which  I  think  the  manufacturing 
pharmacists  have  gone  beyond  their  limit  and  are  trading  on  the  credulity 
of  the  profession  to  the  great  detriment  of  the  public.  The  length  to 
which  organotherapy  has  extended  (not  so  much  on  the  American  side 
of  the  water  as  on  the  European  continent)  beyond  the  legitimate  use 
of  certain  preparations  is  a  notorious  illustration  of  the  ease  with  which 
theoretical  views  place  us  in  a  false  position.  Because  thyroid  extract 
cures  myxedema  and  adrenalin  has  a  powerful  action,  it  has  been  taken 
almost  for  granted  that  the  extract  of  every  organ  is  a  specific  against 
the  diseases  that  affect  it.  This  forcing  of  a  scientific  position  is  most 
hurtful,  and  I  have  known  an  investigator  hestitate  to  publish  results  lest 
they  should  be  misapplied  in  practice.  The  literature  on  the  subject 
issued  by  reputable  houses  indicates,  on  the  one  hand,  the  pseudo-science 
upon  which  a  business  may  be  built  up,  and,  on  the  other,  the  weak- 
minded  state  of  the  profession  on  whose  credulity  these  firms  trade. 
A  second  most  reprehensible  feature  is  the  laudatory  character  of  litera- 
ture describing  the  preparations  which  they  manufacture.  Foisted  upon 
an  innocent  practitioner  by  a  traveling  Autolycus,  the  preparation  is 


THE  TREATMENT  OF  DISEASE  70;^ 

used  successfully,  say,  in  six  cases  of  amenorrhea;  very  soon  a  report 
appears  in  a  medical  journal,  and  a  few  weeks  later  this  report  is  sent 
broadcast  with  the  auriferous  leaflets  of  the  firm.  Some  time  ago  a 
pamphlet  came  from  X  and  Company,  characterized  by  brazen  therapeutic 
impudence,  and  indicating  a  supreme  indifference  to  anything  that  could 
be  called  intelligence  on  the  part  of  the  recipients.  That  these  firms  have 
the  audacity  to  issue  such  trash  indicates  the  state  of  thraldom  in  which 
they  regard  us.  And  I  would  protest  against  the  usurpation  on  the  part 
of  these  men  of  our  function  as  teachers.  Why,  for  example,  should 
Y  and  Company  write  as  if  they  were  directors  of  large  genitourinary 
clinics  instead  of  manufacturing  pharmacists?  It  is  none  of  their  busi- 
ness what  is  the  best  treatment  for  gonorrhea — by  what  possibility  could 
they  ever  know  it,  and  why  should  their  literature  pretend  to  the  com- 
bined wisdom  of  Neisser  and  Guyon?  What  right  have  Z  and  Company 
to  send  on  a  card  directions  for  the  treatment  of  anemia  and  dyspepsia, 
about  which  subjects  they  know  as  much  as  an  unborn  babe,  and,  if 
they  stick  to  their  legitimate  business,  about  the  same  opportunity  of 
getting  information?  For  years  the  profession  has  been  exploited  in 
this  way,  until  the  evil  has  become  unbearable,  and  we  need  as  active 
a  crusade  against  pseudo-science  in  the  profession  as  has  been  waged  of 
late  against  the  use  of  quack  medicines  by  the  public.  We  have  been 
altogether  too  submissive,  and  have  gradually  allowed  those  who  should 
be  our  willing  helpers  to  dictate  terms  and  to  play  the  role  of  masters. 
Far  too  large  a  section  of  the  treatment  of  disease  is  today  controlled 
by  the  big  manufacturing  pharmacists,  who  have  enslaved  us  in  a  plausi- 
ble pseudo-science.  The  remedy  is  obvious :  give  our  students  a  first- 
hand acquaintance  with  disease,  and  give  them  a  thorough  practical 
knowledge  of  the  great  drugs,  and  we  will  send  out  independent,  clear- 
headed, cautious  practitioners  who  will  do  their  own  thinking  and  be 
no  longer  at  the  mercy  of  a  meretricious  literature  which  has  sapped  our 
independence. 

Having  confessed  some  of  our  weaknesses,  I  may  with  better  grace 
approach  the  burning  question  of  the  day  in  the  matter  of  treatment.  An 
influenza-like  outbreak  of  faith-healing  seems  to  have  the  public  of  both 
continents  in  its  grip.  It  is  an  old  story — the  oldest,  indeed,  in  our 
history — and  one  in  which  we  have  a  strong  hereditary  interest,  since 
scientific  medicine  took  its  origin  in  a  system  of  faith-healing  beside 
which  all  our  modern  attempts  are  feeble  imitations.  Lincoln's  favorite 
poem,  beginning  "  We  think  the  same  thoughts  that  our  fathers  have 
thought,"  expresses  a  tendency  in  the  human  mind  to  run  in  circles. 
Once  or  twice  in  each  century  the  serpent  entwining  the  staff  of  ^scula- 
pius  gets  restless,  untwists,  and  in  his  gambols  swallows  his  tail,  and 


704  THE  TREATMENT  OF  DISEASE 

at  once  in  full  circle  back  upon  us  come  old  thoughts  and  old  prac- 
tices, which  for  a  time  dominate  alike  doctors  and  laity.  As  a  profes- 
sion we  took  origin  in  the  cult  of  ^sculapius,  the  gracious  son  of 
Apollo,  whose  temples,  widespread  over  the  Greek  and  Roman  world, 
were  at  once  magnificent  shrines  and  hospitals,  with  which  in  beauty 
and  extent  our  modern  institutions  are  not  to  be  compared.  Amid  lovely 
surroundings,  chosen  for  their  salubrity,  connected  usually  with  famous 
springs,  they  were  the  sanatoriums  of  the  ancient  world.  The  ritual  of 
the  cure  is  well  known,  and  has  been  beautifully  described  by  Walter 
H.  Pater  in  "  Marius  the  Epicurean"  (Macmillan,  New  York,  1907). 
Faith  in  the  god,  suggestion,  the  temple  sleep  and  the  interpretation 
of  its  dream  were  the  important  factors.  Hygienic  and  other  measures 
were  also  used,  and  in  the  guild  of  secular  physicians  which  grew  up 
about  the  temples  scientific  medicine  took  its  origin.  No  cult  resisted 
so  long  the  progress  of  Christianity;  and  so  imbued  were  the  people 
with  its  value,  that  many  of  the  practices  of  the  temple  were  carried 
on  into  the  Christian  ritual.  The  temple  sleep  and  the  interpretation 
of  its  dreams  were  continued  long  into  the  Middle  Ages,  and,  indeed, 
have  not  yet  disappeared.  The  popular  shrines  of  the  Catholic  Church 
today  are  in  some  ways  the  direct  descendants  of  this  ^sculapian  cult, 
and  the  cures  and  votive  oflferings  at  Lourdes  and  St.  Anne  are  in  every 
way  analogous  to  those  of  Epidaurus. 

As  I  before  remarked,  credulity  in  matters  relating  to  disease  remains 
a  permanent  fact  in  our  history,  uninfluenced  by  education.  But  let  us 
not  be  too  hard  on  poor  human  nature.  Even  Pericles,  most  sensible 
of  men,  when  on  his  deathbed,  allowed  the  women  to  put  an  amulet 
about  his  neck.  And  which  one  of  us,  brought  up  from  childhood  to 
invoke  the  aid  of  the  saints  and  seek  their  help — which  one  of  us 
under  these  circumstances,  living  today  in  or  near  Rome,  if  a  dear 
child  were  sick  unto  death,  would  not  send  for  the  Santo  Bambino, 
the  Holy  Doll  of  the  Church  of  Ara  Coeli?  Has  it  not  been  working 
miracles  these  four  hundred  years?  The  votive  offerings  of  gold  and 
of  gems  from  the  happy  parents  cover  it  completely,  and  about  it  are 
grateful  letters  from  its  patients  in  all  parts  of  the  world.  No  doll 
so  famous,  no  doll  so  precious!  No  wonder  it  goes  upon  its  ministry 
of  healing  in  a  carriage  and  pair,  and  with  two  priests  as  its  compan- 
ions! Precious  perquisite  of  the  race,  as  it  has  been  called,  with  all 
its  dark  and  terrible  record,  credulity  has  perhaps  the  credit  balance 
on  its  side  and  in  the  consolation  afforded  the  pious  souls  of  all  ages 
and  of  all  climes,  who  have  let  down  anchors  of  faith  into  the  vast 
sea  of  superstition.  We  drink  it  in  with  our  mother's  milk,  and  that 
is   indeed   an   even-balanced    soul    without    some   tincture.      We   must 


THE  TREATMENT  OF  DISEASE  705 

acknowledge  its  potency  today  as  effective  among  the  most  civilized 
people,  the  people  with  whom  education  is  the  most  widely  spread,  yet 
who  absorb  with  wholesale  credulity  delusions  as  childish  as  any  that 
have  ever  enslaved  the  mind  of  man. 

Having  recently  had  to  look  over  a  large  literature  on  the  subject 
of  mental  healing,  ancient  and  modern,  I  have  tried  to  put  the  matter 
as  succinctly  as  possible.  In  all  ages  and  in  -all  climes  the  prayer  of 
faith  has  saved  a  certain  number  of  the  sick.  The  essentials  are  first 
a  strong  and  hopeful  belief  in  a  dominant  personality,  who  has  varied 
naturally  in  different  countries  and  in  different  ages,  Buddha  in  India, 
and  in  Japan,  where  there  are  cults  to  match  every  recent  vagary ;  yEscu- 
lapius  in  ancient  Greece  and  Rome ;  our  Saviour  and  a  host  of  saints  in 
Christian  communities;  and  lastly,  an  ordinary  doctor  has  served  the 
purpose  of  common  humanity  very  well.  Faith  is  the  most  precious 
asset  in  our  stock-in-trade.  Once  lost,  how  long  does  a  doctor  keep  his 
clientele?  Secondly,  certain  accessories — a  shrine,  a  grotto,  a  church, 
a  temple,  a  hospital,  a  sanatorium — surroundings  that  will  impress  favor- 
ably the  imagination  of  the  patient.  Thirdly,  suggestion  in  one  of  its 
varied  forms — whether  the  negation  of  disease  and  pain,  the  simple 
trust  in  Christ  of  the  Peculiar  People,  of  the  sweet  reasonableness  of  the 
psychotherapeutist.  But  there  must  be  the  will-to-believe  attitude  of 
mind,  the  mental  receptiveness — in  a  word,  the  faith  which  has  made 
bread  pills  famous  in  the  history  of  medicine.  We  must,  however, 
recognize  the  limitations  of  mental  healing.  Potent  as  is  the  influence 
of  the  mind  on  the  body,  and  many  as  are  the  miracle-like  cures  which 
may  be  worked,  all  are  in  functional  disorders,  and  we  know  only  too 
well  that  nowadays  the  prayer  of  faith  neither  sets  a  broken  thigh  nor 
checks  an  epidemic  of  typhoid  fever. 

What  should  be  the  attitude  of  the  clergy,  many  of  whom  have 
been  drawn  into  the  vortex  of  this  movement?  I  feel  it  would  be  very 
much  safer  to  hand  over  this  problem  to  us.  It  is  not  a  burden  which 
we  should  ask  a  hard-working  and  already  overwrought  profession  to 
undertake  or  to  share.  It  might  be  a  different  matter  if  it  were  really 
a  gift  of  healing  in  the  apostolic  sense,  but  we  know  this  was  associated 
with  other  signs  and  wonders  at  present  conspicuous  by  their  absence. 
Then  think  of  the  possibilities  of  self-deception — of  the  saintly  Edward 
Irving  and  the  gift  of  tongues;  of  Monsieur  de  Paris,  the  French  priest, 
and  the  miracles  at  his  tomb,  to  the  truth  of  which  two  fine  quarto 
volumes,  with  "before  and  after"  pictures,  attest!  The  less  the  clergy 
have  to  do  with  the  bodily  complaints  of  neurasthenic  and  hysterical 
persons  the  better  for  their  peace  of  mind  and  for  the  reputation  of 
the  Cloth,     As  wise  old  Fuller  remarked,.  Circe  and  yEsculapius  were 


7o6  THE  TREATMENT  OF  DISEASE 

brother  and  sister,  and  the  wiles  of  the  one  are  very  apt  to  entrap  the 
wisdom  of  the  other. 

Ill 

It  adds  immensely  to  the  interest  in  life  to  live  in  the  midst  of 
these  problems  which  concern  us  so  closely.  We  must  meet  them  with 
an  intelligent  cheerfulness,  in  the  full  confidence  that  the  Angel  of 
Bethesda  never  stirred  the  waters  without  happy  results.  It  is  for  us 
to  see  that  the  soldiers  we  are  training  for  the  fight  against  disease, 
bodily  and  mental,  are  well  equipped  for  the  battle;  and  let  me  briefly, 
in  conclusion,  indicate  how  I  believe  we  should  teach  the  art — the  man- 
agement of  patients  and  the  cure  of  disease.  To  know  how  to  deal  with 
disease  is  the  final  goal,  to  reach  which  the  whole  energies  of  the  student 
should  be  directed.  We  all  recognize  that  it  is  in  the  out-patient  depart- 
ments and  in  the  wards — I  wish  I  could  add  in  the  homes  of  the  general 
practitioners — that  he  must  get  this  part  of  his  training,  not  in  an  elab- 
orate course  of  lectures  on  the  properties  and  action  of  drugs.  In  the 
congested  curriculum  it  is  by  no  means  easy  to  find  the  proper  amount 
of  time  for  this,  the  most  essential  part  of  his  education.  But  as  we 
learn  the  futility  of  the  lecture  room  as  an  instrument  of  teaching  men 
the  Art,  so,  I  think,  we  shall  gradually  be  able  to  adapt  the  courses  so 
that  plenty  of  time  may  be  given  to  the  practical  study  of  the  treatment 
of  cases  under  skilled  direction.  We  should  take  over  to  the  hospital 
of  the  school  the  whole  subject  known  in  the  curriculum  as  therapeutics. 
The  composition  of  drugs,  the  method  of  their  preparation,  and  the  study 
of  their  physiological  action  should  be  taught  in  practical  classes  in  the 
pharmaceutical  laboratories.  In  the  out-patient  departments  and  in  the 
wards  much  more  systematic  practical  instruction  should  be  given  how 
to  treat  disease  and  how  to  manage  patients.  If  we  could  only  get  the 
students  for  a  sufficiently  long  period  in  the  hospital,  what  helpful 
courses  could  be  arranged  in  the  senior  years!  Certain  aspects  of  the 
subject  must  be  ever  kept  before  the  assistants  *  and  the  students,  con- 
sidered, perhaps,  by  different  men  associated  with  the  clinic  according 
to  the  special  capacity  of  each  one.  The  fundamental  law  should  be 
ingrained  that  the  starting-point  of  all  treatment  is  in  the  knowledge 
of  the  natural  history  of  a  disease.  Typhoid  fever,  tuberculosis,  pneu- 
monia, and,  where  possible,  malaria,  should  be  used  for  this  important 
lesson,  and  in  the  everyday  routine  observation  of  cases  the  student 
would  learn  to  know  the  course  of  the  disease,  its  obvious  features,  the 

*  A  post-graduate  course  in  medical  pedagogy  would  be  most  helpful  organized  by 
five  or  six  of  the  large  colleges  and  conducted  by  them  in  rotation  with  teachers  selected 
from  the  different  schools.  Many  able  young  fellows  take  years  to  acquire  methods  to 
which  they  might  be  introduced  m  a  six  months'  course. 


THE  TREATMENT  OF  DISEASE  707 

complications  likely  to  arise;  and  he  would  be  taught  how  to  discrimi- 
nate between  the  important  and  the  unimportant  symptoms  of  a  case. 
This  work  should  form  the  very  basis  of  his  course  in  medicine,  and 
it  should  be  accompanied  by  a  seminar  to  take  the  place  of  set  lectures, 
in  which  the  features  of  all  the  common  diseases  would  be  discussed. 

The  hygienic  and  dietetic  management  of  patients  has  now  come  to 
be  such  a  prominent  part  of  the  w^ork  of  our  hospitals  that  the  student 
may  become  acquainted  with  the  open-air  treatment,  the  various  modifi- 
cations of  diet  suitable  to  different  diseases,  and  the  use  of  massage, 
electricity,  and  other  physical  agents.  But  too  often  he  is  allowed  to 
pick  up  this  information  in  a  haphazard,  irregular  fashion.  One  assist- 
ant of  the  clinic  should  be  detailed  to  see  that  every  member  of  the 
class  knows,  for  example,  how  to  arrange  the  open-air  treatment  for  a 
tuberculous  patient,  and  how  to  supervise  the  diet  of  a  diabetic  case. 
The  student  should  prepare  personally  the  various  nutritive  enemata, 
and  be  able  to  give  the  different  kinds  of  massage,  and  I  would  have 
him  thoroughly  versed  in  all  branches  of  hydrotherapy.  A  serious  diffi- 
culty is  that  nowadays  the  nurse  does  a  great  many  things  that  it  is 
essential  the  medical  student  should  know  how  to  do — the  administra- 
tion of  hypodermics,  the  giving  of  a  cold  pack,  etc. 

Much  more  attention  should  be  paid  to  the  important  subject  bf 
psychotherapy.  It  is  not  every  teacher  who  has  a  special  gift  for  this 
work,  but  if  the  professor  himself  does  not  possess  it,  he  should,  at  any 
rate,  have  sense  enough  to  have  an  assistant  familiar  with  and  inter- 
ested in  the  modern  methods.  How  many  of  our  graduates  have  been 
shown  how  to  carry  out  a  Weir-Mitchell  treatment  or  to  treat  a  patient 
by  suggestion?  The  student  should  be  taught  that  the  very  environ- 
ment of  a  well-managed  clinic  is  in  itself  an  important  factor  in  psychical 
treatment.  A  Philadelphia  friend  once  jokingly  defined  my  practice  at 
the  Johns  Hopkins  Hospital  as  a  mixture  of  hope  and  nux  vomica,  and 
the  grain  of  truth  in  this  statement  lies  in  the  fact  that  with  many  hos- 
pital patients  once  we  gain  their  confidence  and  inspire  them  with  hope, 
the  battle  is  won. 

And  lastly,  from  the  day  the  student  enters  the  hospital  until  grad- 
uation, he  should  study  under  skilled  supervision  the  action  of  the  few 
great  drugs.  Which  are  they?  I  am  not  going  to  give  away  my  list. 
A  story  is  told  that  James  Jackson,  when  asked  which  he  considered 
the  greatest  drugs,  replied :  "  Opium,  mercury,  antimony  and  Jesuit's 
bark;  they  were  those  of  my  teacher,  Jacob  Holyoke."  "Yes,"  replied 
his  interlocutor,  "  and  they  were  those  of  Holyoke's  master,  James 
Douglas,  in  the  early  part  of  the  eighteenth  century."  Mine  is  a  much 
longer  one!     The  student  should  follow  most  carefully  the  action  of 


7o8  THE  TREATMENT  OF  DISEASE 

those  drugs  the  pharmacology  of  which  he  has  worked  out  in  the  labora- 
tory. He  should  be  sent  out  from  the  hospital  knowing  thoroughly  how 
to  administer  ether  and  chloroform.  He  should  know  how  to  handle 
the  various  preparations  of  opium.*  Each  ward  should  have  its  little 
case  with  the  various  preparations  of  the  ten  or  twelve  great  drugs, 
and  when  the  teacher  talks  about  them  he  should  be  able  to  show  the 
preparations.  He  should  study  with  special  care  the  action  of  digitalis 
on  the  circulation  in  cases  of  heart  disease.  He  should  know  its  litera- 
ture, from  Withering  to  Cushney.  It  should  be  taken  as  the  typical 
drug  for  the  study  of  the  history  of  therapeutics — the  popular  phase,  as 
illustrated  by  the  old  woman  who  with  it  cured  the  Principal  of  Bra- 
senose;  the  empirical  stage,  introduced  by  Withering  in  his  splendid 
contribution,  a  model  of  careful  work  of  which  every  senior  student 
should  know;  and  the  last  stage,  the  scientific  study  of  the  drug,  which 
he  will  already  have  made  in  the  pharmacological  laboratory.  He  should 
day  after  day  personally  give  a  syphilitic  baby  inunctions  of  mercury; 
he  should  give  deep  injections  of  calomel  and  he  should  learn  the  history 
of  the  drug  from  Paracelsus  to  Fournier.  He  should  know  everything 
relating  to  the  iodides  and  the  bromides,  and  should  present  definite 
reports  on  cases  in  which  he  has  used  them.  He  must  know  the  use 
of  the  important  purgatives,  and  he  should  have  a  thorough  acquaintance 
with  all  forms  of  enemata.  He  should  know  cinchona  historically,  its 
derivatives  chemically,  and  its  action  practically.  He  should  study  the 
action  of  the  nitrites  with  the  blood  pressure  apparatus,  and  he  should 
over  and  over  again  have  tested  for  himself  the  action,  or  the  absence 
of  action,  of  strychnine,  alcohol,  and  other  drugs  supposed  to  have  a 
stimulating  action  on  the  heart  and  blood  vessels.  While  I  would,  on 
the  one  hand,  imbue  him  with  the  firmest  faith  in  a  few  drugs,  "  the 
friends  he  has  and  their  adoption  tried,"  on  the  other  hand,  I  would 
encourage  him  in  a  keenly  skeptical  attitude  towards  the  pharmacopeia 
as  a  whole,  ever  remembering  Benjamin's  Franklin's  shrewd  remark 
that  "  he  is  the  best  doctor  who  knows  the  worthlessness  of  the  most 
medicines."  You  may  well  say  this  is  a  heavy  contract,  and  one  which 
it  is  impossible  to  carry  out.  Perhaps  it  is  with  our  present  arrange- 
ments, but  this  is  the  sort  of  work  which  the  medical  student  has  a  right 
to  expect,  and  this  is  what  we  shall  be  able  to  give  him  when  in  his 
senior  years  we  give  up  lecturing  him  to  death,  and  when  we  stop  trying 
to  teach  him  too  many  subjects. 

♦Sydenham  obtained  the  appellation  "  Opiophilos "  (Ogle);  and  the  best  prac- 
titioner is  the  man  who  knows  best  how  to  use  "  God's  own  medicine,"  as  it  has  been 
called. 


CHAPTER  XVIII 

THE  PREVENTION  AND  CONTROL  OF  ACUTE 
RESPIRATORY  INFECTIONS 

By  JOSEPH  A.  CAPPS 

Table  of  Contents 

Introduction 7^9 

Transmission  of  Respiratory  Disease /lo 

Routes  of  Transmission 7^3 

Factors  Influencing  Spread  of  Respiratory  Infections   .       .       -715 
Preventive   Measures 7io 

Introduction 

Respiratory  infections  and  their  prevention  have  assumed  a  place  of 
first  importance  in  medicine  as  a  result  of  the  vast  epidemics  in  the 
World  War.  The  medical  history  of  the  war  will  bring  out  two  sur- 
prising facts:  first,  the  rarity  of  gastrointestinal  infections;  second,  the 
frequency  of  respiratory  infections.  In  former  wars  infections  of  the 
alimentary  tract,  such  as  typhoid  and  dysentery,  were  responsible  for  the 
great  epidemics.  In  our  military  camps  of  today  typhoid  and  para- 
typhoid are  curiosities  and  dysentery  is  an  exceptional  occurrence.  The 
disappearance  of  this  formidable  group  of  diseases  can  be  attributed  in 
part  to  the  general  use  of  typhoid  inoculation  and  in  large  measure  to 
the  safeguarding  of  the  drinking  water  from  contamination.  During 
the  Spanish-American  War  the  danger  arising  from  polluted  water  was 
well  known,  but  nevertheless  careful  and  comprehensive  methods  of 
protection  were  not  carried  out.  Today  an  army  digs  its  own  wells, 
builds  reservoirs,  subjects  the  water  to  frequent  bacteriological  tests,  and 
in  other  ways  rigidly  and  scientifically  applies  this  knowledge.  No 
expense  is  too  lavish,  no  effort  too  great  to  provide  this  assurance  of 
soldiers  against  water-borne  infections,  and  the  resuhs  abundantly  justify 
the  expenditure.  The  campaign  against  insect-borne  diseases  has  been 
prosecuted  with  similar  intelligence  and  diligence.  The  destruction  of 
flies  and  mosquitoes,  and  their  breeding-places,  and  the  persistent  war- 
fare against  the  body  louse,  has  almost  rid  the  army  of  malaria,  yellow 
fever,  and  trench  fever. 

709 


7IO     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

Contrast  these  brilliant  results  with  our  experience  in  the  manage- 
ment of  respiratory  infections.  Influenza,  measles,  pneumonia  and 
streptococcus  infections  flourish  and  spread  without  let  or  hindrance,  both 
in  military  and  civil  communities.  A  multitude  of  precautions  are  em- 
ployed and  enforced  with  laxity  or  strictness  according  to  the  individual 
bias  of  officials,  but  apparently  these  diseases  are  checked  only  by  the 
exhaustion  of  susceptible  human  material. 

The  history  of  successful  control  of  any  infection  reveals  the 
important  truth  that  the  manner  in  which  the  virus  gains  entrance  into 
the  body  must  be  known.  The  causative  germ  need  not  be  identified  in 
order  to  work  out  efficient  prevention.  The  attack  on  yellow  fever  was 
most  complicated  and  quite  unavailing  until  it  was  discovered  that  the 
virus  entered  the  body  only  through  the  bite  of  the  mosquito.  After  this 
knowledge  was  obtained,  although  the  germ  was  still  unknown,  the 
methods  of  prevention  became  direct,  simple  and  effective. 

Therefore,  the  most  intensive  study  should  be  directed  to  definite 
understanding  of  the  portals  of  entry  and  the  means  of  conveyance  of 
the  virus  of  infection  in  order  to  insure  success  in  its  control  or 
prevention. 

So-called  Acute  Respiratory  Infections 

The  classification  of  this  group  is  somewhat  arbitrary  and  provisional 
and  includes  the  majority  of  the  contagious  diseases;  namely,  influenza, 
pneumonia,  measles,  whooping  cough,  mumps,  meningitis,  diphtheria, 
scarlet  fever,  septic  sore  throat,  acute  pulmonary  tuberculosis  as  well  as 
ordinary  colds  and  bronchitis.  Some  of  these  infections  are,  strictly 
speaking,  not  in  the  respiratory  tract.  Thus  mumps  affects  the  ducts 
leading  from  the  mouth  to  the  salivary  glands.  Septic  sore  throat  affects 
tonsils  and  pharynx,  which  form,  as  it  were,  a  crossing  of  the  respiratory 
and  digestive  highways.  But  it  is  supposed  that  these  infections  are 
governed  by  the  same  laws  of  transmission  as  the  true  respiratory  infec- 
tions and  until  proof  to  the  contrary  is  offered  they  are  included.  It  is 
worthy  of  note  that  the  specific  germs  of  all  these  diseases  have  been 
identified  with  the  exception  of  scarlet  fever,  measles,  influenza,  and 
perhaps  the  ordinary  colds  and  bronchitis. 

Transmission  of  Respiratory  Diseases 

Our  notions  concerning  the  transmission  of  the  acute  respiratory 
infections  are  founded  too  much  on  traditional  ideas  and  too  little  on 
experimental  evidence.  We  are  warranted  in  assuming  that  the  germs 
pass  from  the  infected  to  the  healthy  individual;  but  in  what  way?    Are 


TRANSMISSION  OF  RESPIRATORY  DISEASES        711 

they  carried  by  the  droplets  of  sputum ;  by  the  expired  air ;  by  particles  of 
dried  sputum  in  the  dust;  by  contact  of  hands  and  dishes;  by  food  and 
drink;  by  kissing;  by  drinking  cups?  If  the  germs  can  travel  by  all 
these  routes,  then  it  is  important  to  determine  the  route  that  is  most 
common,  in  order  that  our  efiforts  at  control  may  be  well  balanced. 

Tuberculosis  has  been  the  subject  of  more  intensive  study  than  any 
other  infection,  Koch's  discovery  of  the  tubercle  bacillus  and  the  uni- 
versal prevalence  of  the  disease  have  been  stimuli  to  a  legion  of  investi- 
gators, both  clinical  and  experimental.  It  is  generally  regarded  as  a 
respiratory  infection,  but  the  ordinary  chronic  cases  may  well  be  excluded 
from  the  group  of  acute  diseases  under  discussion.  The  chronicity  of 
tuberculosis,  the  absence  of  any  definite  incubation  period,  the  latency  of 
its  lesions  and  the  resistance  of  the  bacillus  to  destructive  influences  out- 
side the  body,  all  these  factors  render  the  study  of  transmission  more 
difficult  than  in  the  acute  respiratory  infections.  They  likewise  greatly 
complicate  preventive  measures,  because  any  precautions  to  be  effective 
must  be  continued  over  a  long  period  of  time.  Nevertheless  there  is  much 
to  be  learned  in  reviewing  the  methods  and  conclusions  of  the  great 
scientists  who  for  years  have  endeavored  to  solve  the  riddle  of  the  trans- 
mission of  the  bacilli  of  tuberculosis  (^). 

The  chief  source  of  infection  is  the  sputum  of  tuberculous  human 
beings,  but  man  may  become  infected  also  with  bovine  bacilli  from  the 
meat  and  milk  of  tuberculous  cows.  The  princip^al  modes  of  infection 
that  have  been  championed  can  here  be  only  summarized : 

1.  The  theory  of  ingestion  was  advocated  by  Chauveau  and  Gerlach, 
who  demonstrated  that  both  contaminated  meat  and  milk  were  capable 
of  infecting  man.  The  universal  custom  of  cooking  meat  almost  elimi- 
nates this  source.  Further  investigations  have  shown  that  fifteen  to 
twenty  per  cent,  of  tuberculosis  in  childhood  are  of  bovine  origin  and 
may  be  attributed  in  large  part  to  the  use  of  infected  milk. 

2.  The  theory  of  inhalation  of  dried  dust  was  put  forward  by  Cornet 
and  his  associates,  and  was  made  plausible  by  the  finding  of  living  bacilli 
in  the  dust  on  floors,  walls  and  furniture.  When,  however,  it  was 
shown  that  sunlight  destroys  even  the  hardy  tubercle  bacillus  in  a  state 
of  pulverization,  this  mode  of  transmission  seemed  less  probable. 

3.  The  theory  of  droplet  infection  was  offered  by  Fliigge,  who  suc- 
ceeded in  infecting  animals  by  direct  exposure  to  the  coughing  of  con- 
sumptives. Koch  endorsed  this  hypothesis  and  considered  that  the  tuber- 
culous virus  is  communicated  from  phthisical  patients  to  the  healthy  by 
means  of  particles  of  sputum  expelled  in  coughing. 

4.  The  theory  of  mouth  and  throat  infection  combines  and  includes 
both  the  ingestion  and  inhalation  methods.     It  differs  from  both  in  that 


712     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

it  lays  great  stress  on  the  transmission  of  sputum  to  the  mouth  by  the 
hands,  eating  and  drinking  utensils,  etc.  Also  it  emphasizes  the  frequency 
of  primary  invasion  of  the  tonsils  and  throat  in  distinction  to  primary 
invasion  of  lungs  or  intestines.  Krause  favors  this  theory  above  the 
others.  He  believes  the  spraying  experiments  of  Fliigge  were  not  rigidly 
controlled,  since  the  mouth  was  sprayed  as  well  as  the  nose.  Recently, 
however,  Rogers  (^)  has  wrapped  guinea  pigs  completely  in  cloth,  includ- 
ing the  mouth,  and  subjected  them  to  a  spray  of  finely  divided  particles 
of  sputum.  Invariably  they  contracted  pulmonary  tuberculosis  in  a  few 
weeks. 

From  a  review  of  these  investigations  we  may  conclude  that :  many 
persons  are  infected  in  childhood  through  the  milk  of  tuberculous  cows; 
many  by  means  of  sputum  droplets  coughed  into  the  mouth  and  nose;  a 
small  number  by  inhalation  of  dry  contaminated  dust;  an  unknown 
number  by  means  of  mouth  infection  through  the  medium  of  contami- 
nated hands  and  utensils.  The  factors  concerned  in  the  transmission 
of  tuberculosis  must  all  receive  due  consideration  in  any  study  of  the 
acute  respiratory  infections. 

Sources  of  Infection  in  Acute  Respiratory  Diseases 

The  infective  virus  is  known  to  be  in  the  mucous  secretions  of  the 
mouth,  throat,  bronchial  tubes  or  nose  in  all  of  the  so-called  acute  respira- 
tory infections;  namely,  pneumonia,  influenza,  measles,  mumps,  strepto- 
coccus infections,  diphtheria,  scarlet  fever,  septic  sore  throat,  whooping 
cough,  and  the  common  colds.  This  affords  a  safe  starting-point  for  the 
study  of  transmission.  The  blood  in  a  few  diseases  may  also  contain  the 
pathogenic  germs;  e.g.  in  pneumonia  and  streptococcus  infections,  but 
there  is  no  evidence  that  these  infections  are  ever  communicated  through 
the  medium  of  the  blood  except  possibly  by  invasion  of  wounds.  Open 
wounds  or  mustard  gas  burns  invaded  by  diphtheria  were  believed  to  be 
an  active  source  of  throat  diphtheria  in  hospitals  near  the  front  in  France, 
but  in  civil  life  such  occurrences  are  probably  rare.  Food  and  drink  are 
also  potential  dangers,  but  the  virus  usually  reaches  them  through  the 
medium  of  infected  sputum. 

It  is  safe  to  assume  that  the  ultimate  source  of  infection,  however 
transmitted,  usually  lies  in  the  sputum  or  nasal  secretions.  The  portals 
of  entry  with  few  exceptions  are  the  mouth,  throat,  nose,  and  perhaps 
the  eyes.  These  assumptions  are  tenable  regardless  of  the  different 
theories  of  the  modes  of  communicability. 


TRANSMISSION  OF  RESPIRATORY  DISEASES        713 

Routes  of  Transmission 

The  possible  routes  of  travel  of  infected  mucus  from  sick  to  healthy 
are  numerous  and  much  discussion  has  arisen  over  their  relative 
importance.     They  may  be  classed  as  follows: 

(i)  TJic  Direct  Routes. — (a)  Transmission  by  the  spray  of  mucus 
droplets  from  the  mouth  and  nose  of  the  diseased  to  the  healthy  during 
the  act  of  talking,  coughing  and  sneezing.  Fliigge  (^)  found  that  the 
expired  breath  carried  no  bacteria,  that  talking  expelled  occasional  par- 
ticles of  mucus,  while  sneezing  and  coughing  projected  a  spray  to  a 
distance  of  a  meter.  Doust  and  Lyon  (*)  recovered  bacteria  on  a  Petri 
dish  at  a  distance  of  ten  feet  from  the  person  coughing. 

(b)  Similar  transmission  of  droplets  from  a  "  carrier  "  to  a  healthy 
individual.  The  importance  of  the  carrier  as  a  disseminator  of  contagion 
has  been  more  and  more  emphasized  in  recent  years. 

(c)  Transmission  by  kissing. 

(2)  The  Indirect  Routes. — (a)  Inhalation  of  sputum  in  the  form  of 
dust,  especially  after  dry  sweeping  of  floors,  walks  and  streets.  In  the 
southern  camps  an  increase  in  measles  and  streptococcus  infections  was 
noted  following  dust  storms.  Most  bacteria  die  rapidly  after  drying  and 
exposure  to  sunlight,  so  that  this  danger  may  be  more  apparent  than  real. 

(b)  Hand  to  mouth  infection.  The  patient  coughs  in  his  hand  and 
soils  door  knobs,  pens,  furniture,  or  transmits  the  mucus  to  others  in 
handshaking.  This  virus,  collected  on  the  hands  of  the  healthy,  reaches 
the  mouth  while  wetting  the  fingers  or  eating  and  thus  gains  entrance 
to  the  body. 

(c)  The  use  of  contaminated  canteens,  drinking  cups  and  eating 
utensils.  According  to  Lynch  and  Cummins  {^)  the  custom  of  soldiers 
washing  the  mess  kits  in  a  common  can  of  lukewarm  water  disseminates 
infection,  partly  by  contaminating  the  kits  but  more  particularly  by  trans- 
planting germs  from  the  water  to  the  hands,  which  eventually  find  their 
way  to  the  mouth. 

(d)  Use  of  a  common  wash  basin  or  bowl.  In  hotels  or  camps  the 
wash  basin  is  often  used  for  brushing  the  teeth  or  w'ashing  the  mouth, 
thus  opening  the  way  for  infection  of  the  next  person  who  washes  his 
face  in  the  same  receptacle. 

(e)  Exchange  of  pipes  and  cigarettes,  a  habit  prevalent  among 
soldiers. 

(f)  Food  contaminated  by  diseased  individuals  and  by  carriers. 

(g)  Milk  has  long  been  recognized  as  a  vehicle  for  transmission 
of  infectious  diseases  to  man.  The  first  organisms  found  to  be  carried 
by  milk  were  those  of  typhoid,  dysentery  and  cholera.     Later  on  it  was 


714     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

repeatedly  demonstrated  that  diphtheria,  scarlet  fever  and  septic  sore 
throat  were  disseminated  by  milk.  During  the  last  decade  formidable 
epidemics  of  septic  sore  throat  in  Boston,  Baltimore,  and  Chicago  have 
been  definitely  traced  to  the  milk  supply,  as  well  as  many  smaller  out- 
breaks. 

The  contamination  of  the  milk  supply  with  the  organisms  of  diph- 
theria, scarlet  fever  and  septic  sore  throat  occurs  in  various  ways,  but 
some  of  the  following  conditions  are  usually  associated  with  milk-borne 
epidemics:  (a)  Cases  of  active  infection  or  of  carriers  are  found  among 
the  milkers,  (b)  Cases  of  active  infection  or  of  carriers  exist  among 
the  milk  handlers,  (c)  Milk  vessels,  bottles,  containers,  etc.,  are  infected. 
Sometimes  the  human  agent  is  not  discovered,  but  he  may  be  on  the  farm, 
at  the  collecting  station  or  employed  as  a  distributor.  (d)  Bovine 
mastitis  resulting  from  infection  with  human  pathogenic  germs  is  a 
source  that  is  probably  more  common  than  formerly  supposed.  The  evi- 
dence in  favor  of  scarlet  fever  germs  affecting  the  udders  is  discussed 
by  Savage  (^).  Since  the  causative  organism  of  scarlatina  is  unknown, 
the  question  is  not  capable  of  proof  by  experimentation  and  is  supported 
only  by  the  occurrence  of  garget  and  ulcerated  teats  in  certain  scarlatina 
outbreaks.  Diphtheria  bacilli  of  definite  pathogenic  character  were  found 
by  Ashby  (')  in  ulcers  on  the  teats  of  cows,  during  the  investigation  of  a 
milk-borne  epidemic  of  scarlet  fever,  but  no  instances  of  diphtheria  mas- 
titis have  come  to  the  attention  of  the  writer. 

Septic  streptococcus  sore  throat  has  been  traced  to  bovine  mastitis. 
Strains  of  hemolytic  streptococci,  similar  to  those  found  in  cultures  from 
septic  sore  throat  patients,  have  been  identified  in  milk  of  gargety  cows. 
Experiments  (*)  have  shown  that  streptococci  of  human  origin,  injected 
by  catheter  into  the  udder  of  a  healthy  cow,  will  result  in  mastitis.  After 
producing  an  abrasion  of  the  teat  and  rubbing  in  a  suspension  of  human 
streptococci  an  ascending  infection  of  the  ducts  took  place  finally  invad- 
ing the  udder.  For  several  weeks  thereafter  pus  cells  and  streptococci 
were  present  in  large  number  in  the  milk. 

Theobald  Smith  and  his  co-workers  {^)  believe  that  bovine  mastitis 
due  to  infection  with  strains  of  human  streptococci  may  explain  the 
explosive  nature  of  the  outbreaks.  It  is  probable  that  in  bovine  mastitis 
from  human  streptococci  the  ultimate  source  is  the  sputum  of  the  milker, 
carried  to  the  cow's  teats  by  contaminated  hands.  Mastitis  of  this  type  is 
a  massive  infection,  capable  of  provoking  sudden  and  extensive  outbreaks 
of  sore  throat,  lasting  several  weeks.  How  frequently  epidemics  actually 
spring  from  this  source  can  be  determined  only  by  further  investigatioa 


TRANSMISSION  OF  RESPIRATORY  DISEASES        715 

Factors  Influencing  the  Spread  of  Respiratory  Infections 

The  analysis  of  the  causes  that  are  responsible  for  the  spread  of  these 
diseases  does  not  permit  of  arbitrary  and  dogmatic  conclusions. 
Observers  of  a  given  epidemic  will  frequently  place  a  very  different  value 
on  the  admitted  facts  of  evidence.  Much  is  gained  by  classifying  causes 
into  three  groups:  (i)  factors  concerned  with  proximity;  (2)  factors 
concerned  with  lowered  resistance  or  increased  susceptibility;  (3)  other 
factors. 

The  relative  importance  of  the  first  two  groups  depends,  to  a  degree 
not  generally  appreciated,  on  the  nature  of  the  disease  in  question.  Thus 
Zinsser  (^"')  points  out  that  susceptibility  is  almost  universal  in  certain 
infections;  e.g.  mumps,  measles,  influenza  and  streptococcus  infections. 
Hence  in  these  diseases  proximity  and  contact  are  the  primary  etiological 
elements  of  the  problem  and  susceptibility  plays  a  secondary  role. 

On  the  other  hand  most  individuals  have  a  considerable  resistance 
to  pneumococcus  pneumonia,  meningitis  and  scarlet  fever  even  though 
exposed  to  these  diseases.  Consequently  conditions  tending  to  lower 
resistance  assume  the  greater  importance,  while  proximity  is  of  lesser 
moment. 

No  pretense  is  made  that  causes  falling  in  both  groups  may  not  be 
operative  and  that  often  the  two  may  not  overlap,  but  the  distinction  here 
formulated  will  be  found  useful  for  a  better  valuation  of  factors  and  for 
more  intelligent  application  of  preventive  measures. 

One  must  remember  also  that  the  natural  resistance  of  an  individual 
to  a  disease  such  as  pneumonia  is  quite  broken  down  by  another  ante- 
cedent infection  such  as  influenza  or  measles. 

( I )  Factors  Concerned  with  Proximity. — These  are  most  important 
in  the  diseases  to  which  there  is  an  almost  universal  susceptibility ;  namely, 
influenza,  measles,  streptococcus  infection  and  mumps. 

(a)  Overcrowding  in  civilian  life  and  in  the  military  service  is  the 
bane  of  sanitarians.  Overcrowding  in  camps,  in  hospitals,  at  ports  of 
embarkation,  in  barracks,  and  on  troop  transports  was,  by  common  con- 
sent, the  overwhelming  factor  in  causing  the  great  prevalence  of  respira- 
tory diseases  in  our  army.  In  barracks  the  bunks  were  close  together, 
at  the  mess  tables  men  sat  on  opposite  sides  with  only  three  or  four 
feet  intervening;  in  reading  and  recreation  rooms  and  about  the  stoves 
they  gathered  in  compact  groups ;  in  hospital  wards  with  the  regulation 
provision  of  fifty  beds  there  was  a  space  of  two  feet  between  beds,  but 
in  wards  with  seventy  to  seventy-four  beds,  which  were  the  rule  in  the 
American  Expeditionary  Force  during  the  active  period,  only  five  inches 
separated  the  beds.    On  transports  the  men  in  crowded  sleeping  quarters 


7i6     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

suffered  also  from  a  lack  of  ventilation  and  air  foul  beyond  description. 
The  opportunities,  for  direct  and  indirect  dissemination  were  legion. 

(b)  Promiscuous  dissemination  of  sputum  ami  nasal  secretions  inci- 
dent to  crowding.  This  includes  the  contamination  of  drinking  cups  and 
dishes,  the  conveyance  by  soiled  hands  of  secretions  to  cigarettes,  pipes,  or 
directly  to  the  mouth,  and  the  use  of  a  common  wash  bowl.  All  of  these 
details  of  personal  hygiene  and  cleanliness  are  rendered  difficult  or 
impossible  by  living  in  crowded  quarters. 

(2)  Factors  Concerned  with  Lowered  Resistance. — (a)  Exhausting 
drills  or  long  marches ;  (b)  exposure  to  rain  and  cold ;  (c)  inadequate  bed 
covering;  (d)  poor  ventilation ;  (e)  racial  susceptibility;  (f)  men  from 
rural  homes  are  more  susceptible  to  infectious  diseases  than  those  from 
the  city. 

(3)  Other  Factors. —  (a)  The  failure  to  recognize  and  isolate  early 
cases  of  infection  exposes  others  to  contagion.  Many  army  surgeons 
were  culpable  in  this  respect,  (b)  Failure  to  discover  and  isolate  "  car- 
riers "  of  diphtheria  bacilli  and  meningococci. 

Emerson  (^^)  attributes  the  unfavorable  conditions  responsible  for 
the  high  rate  of  respiratory  infections  in  the  American  Expeditionary 
Force  partly  to  inevitable  limitations  of  transportation  on  land  and  sea 
imposed  by  military  operations  and  reciuirement  of  speed  in  troop  move- 
ments; partly  to  lack  of  labor  and  materials  for  building  shelters;  partly 
to  lack  of  discipline  in  matters  of  personal  hygiene;  and  partly  to  lack 
of  imagination  on  the  part  of  medical  officers  who  subordinate  the  pro- 
tection of  a  community  to  the  symptomatic  treatment  of  the  patient. 

The  Role  of  Carriers 

In  every  epidemic  there  are  many  mild  or  atypical  cases  of  infection 
that  are  not  reported  to  the  health  authorities.  There  are  also  many 
"  carriers  "  or  healthy  individuals  who  harbor  pathogenic  germs  without 
being  infected.  Presumably  the  sick  are  more  liable  to  infect  others  than 
the  carriers,  but  the  sick  are  cjuarantined  while  carriers  are  allowed  their 
freedom.  Thus  carriers  may  become  important  factors  in  the  spread  of 
disease.  Failure  to  control  diphtheria  and  meningitis  epidemics  has  been 
attributed  to  the  neglect  of  carriers. 

Since  carriers  are  often  very  numerous  it  is  not  practicable  to  attempt 
universal  cultures  of  a  community  or  camp.  But  cultures  of  contacts  in 
families,  wards,  or  small  military  organizations  are  desirable,  since  the 
segregation  of  carriers  has  often  been  the  means  of  ending  an  epidemic. 
The  whole  problem  of  carriers  needs  further  investigation,  which  may 
lead  to  radical  changes  in  preventive  medicine. 


TRANSMISSION  OF  RESPIRATORY  DISEASES        717 

The  Importance  of  Cross  Infectioiis 

In  times  of  peace  contagious  hospitals  have  always  been  embarrassed 
by  cross  infections,  especially  of  scarlet  fever  and  diphtheria  or  of 
measles  and  diphtheria.  Frequently  these  cross  infections  have  been  con- 
tracted in  the  hospital.  But  in  our  military  camps  tlie  tremendous 
importance  of  cross  or  multiple  infections  in  the  respiratory  tract  has 
been  for  the  first  time  brought  home  to  the  profession.  Reports  from  our 
home  camps  indicate  that  measles  uncomplicated  was  of  little  danger,  but 
that  the  secondary  invasion  of  streptococci  causing  pneumonia  gave  rise 
to  a  formidable  mortality.  Similarly  in  the  American  Expeditionary 
Force,  influenza  alone  was  rarely  serious.  Most  clinicians  and  bac- 
teriologists are  of  the  opinion  that  the  deadly  pneumonia  following  in 
the  wake  of  influenza  was  due  to  a  secondary  infection  of  streptococcus, 
pneumococcus  or  other  germs.  Multiple  infections  were  the  rule  in 
fatal  cases.  This  so-called  "  polybacterialism  "  finds  its  simplest  explana- 
tion in  promiscuous  transfer  of  infected  secretions  from  one  individual 
to  another.  An  initial  attack  of  measles  or  influenza  renders  the  mouth 
and  air  passages  highly  susceptible  to  other  pathogenic  organisms.  Toxic 
gases  likewise  prepare  the  soil  for  bacterial  growth. 

Cross  infections  may  occur  anywhere,  but  there  are  certain  places 
where  the  combination  of  close  cjuarters  and  the  presence  of  carriers  of 
different  organisms  is  highly  favorable.  Such  places  are:  the  hospital 
trains  where  gas,  influenza,  streptococcus,  pneumococcus  and  wounded 
patients  are  herded  together  in  sitting  compartments  or  placed  in  adja- 
cent bunks ;  the  ambulances  and  the  receiving  wards  where  these  men  are 
again  brought  together  with  new  contacts ;  and  finally  in  the  hospital 
wards.  We  have  repeatedly  observed  the  onset  of  pneumonia  within 
forty-eight  hours  of  the  arrival  of  a  convoy  on  these  trains.  In  civil 
life  cross  infections  are  favored  by  the  living  conditions  in  charitable 
institutions,  college  dormitories  and  public  schools.  The  probability  that 
hospitalization  is  responsible  for  the  dissemination  of  bacteria  is  pointed 
out  by  Cole  ("),  who  found  that  the  number  of  measles  patients  that  on 
admission  to  a  hospital  harbored  streptococcus  hemolyticus  was  small, 
but  that  the  majority  of  these  patients  acquired  the  organism  during  their 
residence  in  the  hospital. 

Levy  and  Alexander  (")  recovered  streptococci  from  the  throats  of 
14.8  per  cent,  of  489  new  recruits,  whereas  95  men  in  one  organization 
that  had  been  in  camp  for  months  yielded  83  per  cent,  positive  cultures. 
Still  more  significant  is  their  observation  that  most  of  the  "  clean  "  cases 
in  measles  wards  acquired  streptococci  within  a  week  from  neighboring 
streptococcus  carriers.     Bronchopneumonia  following  measles  occurred 


7i8     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

exclusively  in  those  patients  who  were  carriers  of  streptococci.  Careful 
studies  of  this  kind  on  cross  infections  in  influenza  are  not  available,  but 
would  probably  give  similar  results.  It  is  not  an  overstatement  to  assert 
that,  in  the  great  epidemics  of  influenza  and  measles  in  the  army  and  in 
civil  hospitals,  cross  or  secondary  infections  with  streptococcus,  pneumo- 
coccus  and  other  organisms  ushered  in  most  of  the  pneumonias  and  were, 
therefore,  responsible  for  a  large  percentage  of  deaths. 

Preventive  Measures 

The  campaign  against  the  epidemics  of  respiratory  infections  so  far 
has  developed  very  little  along  offensive  lines.  It  is  essentially  a  series 
of  defensive  battles,  designed  to  give  protection  to  humans  against  the 
bacterial  weapons  and  to  minimize  the  effect  of  wounds  thereby  inflicted. 
The  methods  of  proved  value  may  be  considered  under  the  following 
classification:  (i)  early  recognition  of  infection;  (2)  prophylactic  vac- 
cination; (3)  destruction  of  pathogenic  germs;  (4)  the  aseptic  method; 
(5)  blocking  transmission  by  physical  means. 

( 1 )  Early  Recognition  of  Infection. — The  immediate  discovery  and 
identification  of  a  case  of  infectious  disease  is  the  keynote  of  success  in 
controlling  an  epidemic.  Prompt  isolation  and  quarantine  of  the  first 
case  during  the  contagious  period  is  more  efficacious  in  stamping  out  the 
disease  than  the  most  elaborate  general  measures  later  on,  when  the  con- 
tagion has  spread  and  become  intrenched  in  many  foci.  Confinement  of 
the  patient  to  bed  simplifies  quarantine  and  renders  it  more  effective,  and 
at  the  same  time  secures  to  the  individual  his  maximum  power  of 
resistance. 

(2)  Prophylactic  Vaccination. — Antidiphtheria  inoculation  by  the 
toxin-antitoxin  method  marks  a  great  advance  in  the  control  of  diph- 
theria. The  immunizing  process  requires  several  weeks  and  is  most 
advantageously  employed  among  the  children  of  the  crowded  cities  where 
diphtheria  is  endemic.  Zingher  (^*)  advocates  its  more  general  use  in 
young  children  as  the  best  i-neans  of  eliminating  the  existing  prevalence  of 
the  disease.  For  the  immediate  protection  of  individuals  exposed  to 
infection  the  single  dose  of  prophylactic  antitoxin  affords  an  immunity 
lasting  several  weeks  and  because  of  its  quick  action  is  the  method  of 
choice. 

In  prophylactic  immunization  against  pneumonia,  some  progress  has 
recently  been  made.  Cecil  and  Austin  (^^)  obtained  encouraging  results 
at  Camp  Upton,  where  12,519  men  were  vaccinated  with  Types  I,  II 
and  III  pneumococcus.  During  an  observation  period  of  ten  weeks  none 
of  these  cases  that  had  received  two  or  more  injections  developed  pneu- 


PREVENTIVE  MEASURES  719 

monia  of  these  three  fixed  types,  whereas  in  a  control  of  about  20,000 
men  unvaccinated  there  were  26  cases  of  pneumonia  of  Types  I,  II  and 
III,  Later,  Cecil  and  Vaughan  (^^)  used  a  lipo vaccine  in  13,460  men  at 
Camp  Wheeler  for  the  same  types  of  pneumococcus.  Although  consid- 
erable protection  was  conferred,  the  prevalence  of  influenza  obscured  the 
effects  of  the  pneumococcic  immunization  and  the  results  were  not  so 
favorable  as  at  Upton.  During  measles,  streptococcus  and  influenza  epi- 
demics Type  IV  pneumococcus  pneumonias  are  numerous  and  up  to  the 
present  time  little  has  been  accomplished  in  preventing  this  formidable 
group  by  vaccination.  Influenza  prophylactic  vaccines  have  been  tried 
with  varying  success  (Rosenow  ("),  McCoy  C^),  but  the  treatment  is 
still  in  the  experimental  stage.  The  other  respiratory  infections  have  so 
far  proven  refractory  to  immunizing  measures. 

(3)  Destruction  of  Pathogenic  Germs. — The  use  of  antiseptic 
gargles  and  sprays  has  had  many  advocates.  Sailer  believes  that  the  daily 
irrigation  of  the  throat  in  hospital  wards  causes  a  marked  diminution  in 
cross  infections.  But  the  disappointing  results  of  these  methods  in 
clearing  up  the  throats  of  carriers  of  diphtheria  bacilli  and  meningococci 
have  undermined  our  confidence  in  their  efiicacy.  The  removal  of  dis- 
eased tonsils  and  adenoids  in  diphtheria  and  meningococcus  carriers  has 
given  excellent  results  in  the  experience  of  Friedberg  (")  and  others  and 
deserves  further  trial. 

If  the  sputum  and  nasal  discharges  could  be  effectively  collected  on 
bits  of  cloth  and  in  sputum  cups  and  burned,  a  definite  source  of  con- 
tagion would  be  eliminated.  The  enforcement  of  this  precaution  in  car- 
riers and  ambulatory  patients  is  extremely  difficult.  All  dishes  and  drink- 
ing vessels  should  be  sterilized  in  boiling  water.  Spitting  about  the 
wards,  on  the  streets,  and  in  public  conveyances  should  be  rigidly  pre- 
vented. The  danger  from  fomites  in  respiratory  infections  is  greatly 
underrated  in  the  opinion  of  no  less  an  authority  than  Chapin  (""),  who 
states :  that  physicians  rarely  carry  disease  from  the  sick  to  the  well ;  that 
infection  by  clothing  is  rare;  and  that  fomites  in  a  room  occupied  by 
scarlet  fever  or  smallpox  are  not  likely  to  convey  contagion.  Upon  this 
general  assumption  the  fumigation  of  rooms  after  occupancy  by  con- 
tagious cases  has  been  limited  or  abandoned  by  many  of  our  municipal 
health  departments.  The  belief  is  strong  that  most  germs  die  or  lose  their 
virulence  soon  after  leaving  the  body. 

(4)  The  Aseptic  Method. — The  aseptic  method  of  "  antisepsie  medi- 
cale  "  was  introduced  by  the  French  for  the  purpose  of  combating  cross 
infections  in  hospitals.  The  method  is  based  on  the  hypothesis  that 
respiratory  infections  are  transmitted  chiefly  by  contact,  dissemination  by 
the  air  being  neglected.    At  the  Pasteur  Hospital  in  Paris,  isolation  in  the 


720     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

ordinary  sense  is  less  emphasized  than  the  aseptic  details  in  the  care  of 
the  sick.  Patients  with  various  contagious  diseases  are  placed  in  adjoin- 
ing rooms.  The  same  nurse  attends  different  diseases,  but  observes  rigid 
precautions  in  wearing  a  gown  that  is  left  in  the  room  and  in  washing  the 
hands  upon  leaving  the  room.  Similar  methods  have  been  successfully 
employed  in  the  care  of  ward  patients  at  the  Monsell  Hospital  in  Man- 
chester (-^),  where  a  sheet-covered  screen  forms  a  barrier  about  each 
bed.  The  nurse  is  required  to  wear  rubber  gloves  whenever  a  patient 
is  handled  and  a  gown  that  is  always  kept  inside.  Wherever  this  idea  has 
been  put  in  practice  rigidly,  cross  infections  have  been  very  few.  No  one 
can  question  the  success  of  the  method. 

But  the  conclusion  that  contact  between  patients  and  nurses  is  the 
essential  and  only  means  of  transmission  overcome  by  these  precautions 
seems  unwarranted.  This  technique  demands  most  rigid  isolation  of 
patient  from  patient  and  the  separation  of  patients  by  partitions  or  screens 
also  prevents  droplet  infection  by  coughing.  From  a  practical  point  of 
view  the  system  is  complicated  and  expensive  as  a  nurse  must  be  highly 
specialized  in  the  technique  by  long  training  before  she  is  competent  to 
take  charge  of  a  ward.  While  freely  admitting  the  efficiency  of  the 
"  aseptic  method,"  we  will  do  well  to  inquire  into  ways  and  means  of 
rendering  it  more  simple  and  economical,  at  the  same  time  retaining  its 
essential  features. 

(5)  Blocking  Transmission  by  Physical  Means. — Could  it  be  proved 
that  droplet  infection  and  direct  contact  were  the  primary  factors  in 
transmission  and  that  indirect  contact  with  sputum,  soiled  hands  and 
objects  were  secondary  factors,  then  our  attention  would  be  focussed  on 
blocking  the  germs  in  their  course  of  travel  from  one  person  to  another. 
The  blocking  method  is  accomplished  principally  by  the  following  means : 

( 1 )  Cubicles  or  separate  rooms.  In  hospital  wards  and  especially 
in  military  hospitals  where  small  rooms  are  often  not  available,  the  sheet 
culiicle,  a  sheet  suspended  on  a  wire  seven  feet  above  the  floor  and  extend- 
ing from  the  head  to  the  foot  of  the  bed,  has  given  universal  satisfaction. 

(2)  Face  masks.  The  gauze  face  mask  has  long  been  employed  by 
surgeons  in  the  operating  room  to  prevent  droplet  infection  of  wounds. 
Strong  ("'")  and  his  associates  worked  with  impunity  among  victims  of 
the  pneumonic  plague  in  Manchuria  by  using  masks  made  of  gauze  rein- 
forced with  cotton.  Meltzer  (~^)  urged  the  use  of  a  fine  net  over  the 
faces  of  patients  with  infantile  paralysis  and  also  over  the  faces  of 
attendants.  To  Weaver  (-*)  belongs  the  credit  of  demonstrating  the 
value  of  the  mask  in  protecting  attendants  and  physicians  from  contract- 
ing infection.  During  a  period  of  eighteen  months  he  succeeded  in  elimi- 
nating scarlet  fever  among  nurses,  whereas  in  the  preceding  twenty-one 


PREVENTIVE  MEASURES  721 

months  eight  per  cent,  had  acquired  the  disease.  x\t  the  same  time  the 
incidence  of  diphtheria  carriers  was  reduced  from  twenty-six  per  cent,  to 
about  five  per  cent. 

Weaver's  method  afiforded  such  apparent  protection  to  the  doctors  and 
nurses  at  the  Base  Hospital  at  Camp  Grant  that  the  author  ("^)  undertook 
the  experiment  of  using  face  masks  on  patients  to  protect  them  against 
cross  infection.  So  long  as  a  patient  remains  isolated  in  the  cubicle,  he  is 
protected;  when  he  leaves  the  cubicle  he  endangers  others,  and  is  himself 
exposed  to  cross  infections.  As  a  result  of  numerous  cross  infections, 
particularly  scarlet  fever,  measles  and  streptococcus,  we  instituted  the 
use  of  the  mask  on  patients  in  all  wards  where  respiratory  infections  were 
treated.  Each  patient  was  issued  daily  a  clean  mask  which  when  not  in 
use  was  pinned  to  his  cubicle  sheet. 

Haller  and  Colwel^"**)  made  a  careful  study  of  various  qualities  and 
thickness  of  gauze  necessary  to  procure  blocking  of  droplets.  They 
advise  the  use  of  five  layers  of  gauze  with  a  32  x  36  mesh  when  worn  by 
the  attendant  only,  and  three  layers  when  worn  by  both  attendant  and 
patient.  The  patients  were  told  that  the  cubicle  is  like  the  dugout  in  a 
gassed  area;  as  long  as  one  remains  inside  the  mask  is  superfluous,  but 
it  is  dangerous  to  leave  the  cubicle  unmasked. 

Since  many  persons  were  exposed  to  both  primary  and  cross  infec- 
tions before  reaching  the  ward  the  following  means  were  adopted.  At 
the  regimental  infirmary  every  case  with  respiratory  infection  was  masked 
as  soon  as  recognized.  .Upon  entering  the  ambulance  every  patient,  sick 
or  well,  was  masked.  In  the  receiving  ward  every  ambulatory  patient 
who  entered  the  hospital  was  masked  at  the  door  and  all  patients  con- 
tinued to  wear  the  mask  until  they  reached  the  shelter  of  their  ward  and 
cubicles. 

Before  the  method  of  masking  patients  was  introduced,  and  the 
cubicle  alone  was  employed,  we  had  ten  instances  of  cross  infection  with 
scarlet  fever  in  wards  occupied  by  other  diseases.  In  four  instances,  or 
forty  per  cent.,  there  were  subsequent  cases  of  scarlet  fever  during  the 
week  of  quarantine.  In  three  wards  where  measles  broke  out  as  a  cross 
infection  there  was  one  ward  in  which  a  subsequent  case  of  measles 
developed  during  the  two  weeks  of  quarantine.  After  masks  were  used 
universally  by  patients  and  attendants,  the  results  were  as  follows :  in 
twenty-four  wards  where  scarlet  fever  appeared  as  a  cross  infection, 
there  was  only  one  ward,  or  five  per  cent.,  in  which  a  subsequent  case 
developed ;  in  twelve  wards  where  measles  occurred  as  a  cross  infection, 
there  were  two  wards,  or  seventeen  per  cent.,  in  which  a  subsequent  case 
developed.  To  summarize :  Before  general  masking,  in  thirteen  wards 
with  cross  infection,  there  were  five  wards,  or  thirty-eight  per  cent,  with 


^22     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

subsequent  cases.  After  masking,  in  thirty-six  wards  with  cross  infec- 
tion, there  were  three  wards,  or  8.3  per  cent.,  with  subsequent  cases.  The 
statistics  in  streptococcus  cross  infections  cannot  be  tabulated,  because 
there  was  no  period  of  quarantine  after  exposure.  It  may  be  significant, 
however,  that  only  twenty  cases  of  bronchopneumonia  developed  in  over 
900  cases  of  measles,  although  streptococcus  infections  were  prevalent. 

The  Limitation  of  Isolation  Measures 

What  measure  of  success  can  be  expected  of  the  isolation  methods 
just  described  in  preventing  the  spread  of  epidemics  of  influenza,  measles 
and  streptococcus  infections  in  civil  communities  and  in  military  camps? 
Can  they  be  depended  on  to  check  the  onward  sweep  of  these  infections? 
The  experience  of  public  health  officers  and  epidemiologists  in  the  army 
shows  very  definitely  that  these  barriers  cannot  withstand  the  irresistible 
advance  of  such  epidemics.  Individuals,  families,  organizations  may  here 
and  there  secure  protection,  but  the  population  as  a  whole  is  submerged. 
The  reason  for  this  failure  is  that  universal  enforcement  of  isolation 
among  healthy  people  or  healthy  troops  is  impossible.  Even  the  infected 
cannot  be  easily  isolated  since  healthy  "  carriers  "  are  always  numerous 
and  cannot  be  recognized  without  taking  cultures  of  all.  The  attempts  to 
rigidly  isolate  healthy  people  wherever  they  congregate  in  civil  life ;  e.g. 
compulsory  masking  as  practiced  in  San  Francisco  in  the  recent  influenza 
outbreak,  would  seem  doomed  to  failure  as  a  general  measure,  although 
doubtless  many  individuals  might  thereby  secure  protection. 

In  army  camps  where  it  is  possible  to  quarantine  large  organizations, 
the  chances  of  success  are  far  greater,  but  in  practice  they  were  often 
disappointing  in  the  case  of  influenza  and  measles,  diseases  in  which 
"  carriers  "  cannot  be  identified  because  cultures  are  of  no  assistance. 
Isolation  in  meningitis  and  diphtheria  yielded  much  better  results  because 
both  sick  and  "  carriers  "  can  be  recognized  by  cultures  of  the  throat. 
The  bald  truth  may  as  well  be  faced,  that  in  the  army,  influenza,  measles, 
mumps  and  streptococcus  infections  spread  rapidly  and  freely  in  spite  of 
all  the  efforts  of  sanitarians. 

Isolation  Methods  in  Control  of  Cross  Infections 

To  stem  the  tide  of  a  highly  contagious  disease  is  one  thing;  to  pro- 
tect healthy  individuals  from  the  disease  and  to  protect  the  sick  from 
cross  infections  is  another.  In  the  first  situation  the  individuals  are  not 
under  personal  control  and  supervision;  in  the  second  situation  the  indi- 
viduals are  under  the  influence  of  personal  discipline.  Isolation  methods 
are  not  at  all  effective  in  checking  the  spread  of  the  most  contagious 
diseases  and  only  partly  effective  in  the  less  contagious  ones.     On  the 


PREVENTIVE  MEASURES 


723 


Barracks 


Mess    Room 


DQDDODDDQ 
DQaDDDDQD 


G 


l§ 


u 


Cubicles  made  by 

stretching  half  of  shelter 

tent  on  one  side  of  bunk 

All  train  patients  masked 
befqre_enterJng_Am]}ulaMce_ . 


U 


■a 


Receiving    Ward 


See  that  Mask  is  on 
all  Patients  admitted 


Culture  Throats  etc. 


00000  00 


0000000 


0000000 


o-- 


Men  all  facing 

same  way 

at  table 


Mask  soldier  in  Barracks  or 
Reg.  Infirviary  as  soon  as 
resp.  infection  is  recognized 


-Mask  all  Ambulance  Cases 


Observation 


QlDlQla 


Waiting  Room 

for 

discharged 

Patients 


•^Duty 


Ward 


Sheet        Face  Masks 
Cubicles  for 


Surgeons, 

Nurses, 

Attendants, 

Patients, 

out  of 

cubicle 


Classified    Resp. 


alDlDia 


Inf.     Ward 


Same  methods 
as  in  Observ.  Ward 


Fig.  I.— Diagram  of  the  Technic  for  the  Control  of  Respiratory 
Cross-Infections  in  Military  Camps 


724     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

other  hand,  isolation  is  capable  of  greatly  reducing  the  incidence  of  cross 
infections.  At  first  blush  the  control  of  cross  infections  appears  to  be  a 
comparatively  insignificant  phase  of  the  problem,  and  it  is  when  expressed 
in  mere  numbers.  But  its  importance  defined  in  terms  of  mortality  is 
very  great,  for  death  usually  follows  in  the  wake  of  cross  infections. 

A  comprehensive  scheme  for  reducing  cross  infections  in  the  army 
is  outlined.  (Fig.  i.)  Most  of  these  measures  have  been  employed 
in  the  service,  but  not  consistently  and  rigidly. 

( 1 )  In  camps  newly  arrived  troops  should  be  segregated. 

(2)  In  the  triage  every  effort  should  be  made  to  keep  the  gas  and 
respiratory  infections  separated. 

(3)  In  hospital  trains  the  patients  should  be  sorted  as  far  as  possible 
to  segregate  all  respiratory  infections.  The  proximity  of  such  patients 
to  gassed  or  wounded  soldiers  should  be  avoided.  Since  minor  throat 
and  bronchial  infections  and  carriers  are  a  menace,  the  stretcher  cases 
should  be  separated  by  a  sheet  partition.  The  nursing  personnel  and 
surgeons  should  wear  masks  when  on  duty. 

(4)  In  barracks  overcrowding  is  to  be  avoided.  The  bunks  should 
be  separated  by  the  half  of  a  shelter  tent  or  other  partition.  As  soon  as 
a  case  of  respiratory  infection  is  recognized  he  should  be  masked  and  sent 
to  the  hospital. 

(5)  In  the  mess  seating  soldiers  at  a  narrow  table  all  facing  the 
same  direction  is  a  simple  and  useful  expedient  for  limiting  the  danger 
of  droplet  infection,  and  has  been  tried  with  success. 

(6)  All  patients  traveling  by  ambulance  should  be  masked. 

(7)  An  orderly  stationed  at  the  entrance  of  the  receiving  ward 
^ould  see  that  every  patient  admitted  is  masked,  unless  he  is  suffering 
from  dyspnea.  The  mask  should  be  worn  until  the  patient  reaches  the 
shelter  of  his  cubicle.  Patients  awaiting  discharge  should  be  kept  sepa- 
rate from  those  awaiting  admission. 

(8)  Separate  wards  are  desirable  for  influenza,  pneumonia  and 
gassed  cases  as  well  as  for  those  diseases  ordinarily  isolated,  such  as 
measles  and  meningitis. 

The  beds  should  be  separated  by  sheet  screens.  The  face  masks 
should  be  worn  by  physicians,  nurses,  ward  men  and  by  all  patients 
when  out  of  their  cubicles.  Within  the  cubicle  the  mask  may  be  removed 
and  pinned  to  the  sheet.  The  patient  should  wear  the  mask  when  leaving 
the  cubicle  at  all  times,  except  in  the  wash  room,  where  only  one  person 
should  enter  at  a  time.  Meals  should  be  eaten  in  the  cubicle,  although  the 
patient,  if  masked,  may  be  allowed  to  carry  his  dishes  from  and  to  the 
kitchen.  Smoking  should  be  prohibited  in  these  wards,  as  it  necessitates 
removal  of  the  mask  and  is  also  harmful  to  the  inflamed  air  passages. 


PREVENTIVE  MEASURES  725 

All  eating  utensils  should  be  sterilized  in  boiling  water  after  each  meal. 
Physicians  and  attendants  after  examining  or  handling  a  patient  should 
wash  the  hands  with  soap  and  water.  Masks  should  be  disinfected  by 
soaking  an  hour  in  two  per  cent,  cresol  solution,  then  by  boiling  half  an 
hour  in  soap  and  water.  In  practice  the  mask  may  owe  much  of  its  value 
to  limiting  the  opportunities  of  hand-to-mouth  infection  as  well  as  to 
direct  droplet  dissemination. 

Control  of  Cross  Infections  in  Civil  Practice 

The  principles  of  prevention  are  the  same  in  civil  as  in  military  prac- 
tice, but  their  application  is  quite  different  owing  to  the  loose  organization 
and  lack  of  discipline  in  civil  communities.  The  immediate  diagnosis 
and  reporting  of  all  contagious  diseases  is  a  fundamental  procedure. 
The  reportable  diseases  should  include  streptococcus  sore  throat,  which 
is  generally  neglected  by  physicians. 

In  carrying  out  isolation  measures  in  the  home  emphasis  should  be 
laid  on  the  danger  of  secondary  infection  to  the  patient  as  well  as  on 
the  spread  of  the  patient's  contagion  to  others.  Especially  in  measles  and 
influenza  the  patient  needs  this  safeguarding,  so  easily  afforded  by  mask- 
ing the  face  of  nurse  and  all  others  entering  the  sick  room  and  the 
insistence  on  cleanliness  of  hands  and  eating  utensils.  In  this  way  there 
is  hope  of  minimizing  the  frequency  of  complicating  pneumonia,  otitis 
media,  etc. 

Hospitalisation 

For  years  our  health  departments  have  believed  that  the  hospitali- 
zation of  all  contagious  diseases  would  bring  about  a  decided  diminution 
of  the  morbidity  rate.  This  has  been  the  motive  for  building  large 
municipal  hospitals  for  contagious  diseases.  According  to  Chapin  the 
results  of  the  movement  have  been  disappointing.  He  states  that  com- 
munities in  which  hospitalization  of  contagious  diseases  has  been  almost 
complete  for  years,  show  quite  as  high  prevalence  of  these  diseases  as 
communities  in  which  there  is  no  attempt  at  hospitalization.  The  bring- 
ing together  under  one  roof  of  many  different  infections  may  actually 
expose  the  patient  to  a  new  disease.  Moreover,  the  healthy  "  carriers  " 
of  infection  are  not  controlled  by  this  method.  In  the  light  of  this 
experience  more  attention  should  be  given  to  the  supervision  of  house 
quarantine,  not  only  by  city  physicians,  but  by  visiting  nurses  capable 
of  instructing  the  family  in  preventive  measures. 


726     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

Closing  of  Public  Places 

During  the  epidemic  of  influenza  the  advisabihty  of  closing  schools, 
theaters,  and  other  places  of  assembly,  was  heatedly  discussed  by  health 
ofificials.  The  danger  of  contagion  was  admitted.  On  the  other  hand  it 
was  urged  that  the  discipline,  regular  hours,  and  good  ventilation  of  the 
schoolroom  afforded  less  exposure  to  disease  than  the  uncontrolled 
mingling  of  children  on  the  streets.  The  belief  is  firmly  rooted  among 
sanitarians  that  proximity  out  of  doors  where  the  air  is  in  constant  move- 
ment is  far  less  liable  to  disseminate  contagion  than  proximity  indoors, 
where  the  air  is  often  stagnant. 

For  sporadic  cases  of  infectious  disease  the  segregation  of  the  patient, 
and  if  possible  of  carriers,  is  sufficient.  When,  however,  an  existing 
epidemic  invades  a  school,  it  is  often  desirable  to  close  its  doors  until 
the  force  of  the  infectious  wave  is  spent.  In  theaters  and  churches  much 
might  be  accomplished  in  checking  transmission  by  direct  appeal  to  the 
audience  to  always  cover  the  mouth  with  a  handkerchief  during  coughing 
and  sneezing — a  practice  introduced  by  a  noted  evangelist.  Teachers 
in  the  schools  and  parents  in  the  home  are  under  obligation  to  instruct 
children  upon  this  matter  of  personal  hygiene. 

Good  ventilation  of  assembly  rooms  materially  lessens  the  liability  of 
germ  dissemination  and  should  receive  more  attention.  The  air  in  public 
libraries,  schoolrooms  and  lecture  halls  where  the  windows  are  closed 
to  exclude  noise  and  smoke  is  often  oppressively  stale,  and  in  conse- 
quence favors  the  spread  of  contagion. 

Special  Measures 

This  chapter  is  intended  to  treat  only  of  the  general  principles  con- 
cerned in  the  control  of  respiratory  infections,  since  specific  therapy  will 
be  discussed  under  the  separate  diseases.  Only  a  few  applications  of 
these  principles  to  individual  infections  need  special  mention. 

Pneumonia. — The  promising  work  on  vaccine  prophylaxis  has  already 
been  referred  to.  Individual  isolation  of  different  types  of  pneumo- 
coccus  infection  in  pneumonia  wards  is  advocated  by  Cole,  but  Zinsser 
considers  this  unessential.  Isolation  for  the  purpose  of  preventing  cross 
infection  with  other  germs,  especially  streptococcus,  is,  however,  of 
undoubted  value. 

Measles  is  a  dangerous  disease  in  proportion  to  the  incidence  of 
secondary  infections.  Hence  the  importance  of  isolation  measures. 
During  the  prevalence  of  streptococcus  infections  the  separation  of 
measles  patients  harboring  streptococci  in  the  throat  from  the  clean  cases 
is  deserving  of  trial.     Isolation  in  the  home  with  rigid  enforcement  of 


PREVENTIVE  MEASURES  -jz-j 

masking  and  cleanliness  on  the  part  of  attendants  should  diminish  the 
frequency  of  pulmonary  and  other  complications. 

Iniluenza  as  a  primary  infection  cannot  be  adequately  controlled  by 
isolation  or  any  other  measures  now  known.  Still  it  is  possible  to  give 
a  large  degree  of  individual  protection  to  the  sick  in  hospitals  by  rigid 
quarantine  and  by  the  prevention  of  secondary  infections. 

Meningitis  and  Diphtheria  demand  a  search  for  carriers  among  con- 
tacts by  means  of  throat  cultures.  The  isolation  of  contacts  leads  to  the 
questionable  quarantine  of  many  persons  with  positive  cultures.  There  is 
need  of  discretion  in  avoiding  promiscuous  culturing  of  organizations 
beyond  the  immediate  focus  of  the  disease  and  also  in  releasing  carriers 
of  non-virulent  diphtheria  bacilli.  Immunization  of  contacts  yielding  a 
positive  Schick  test  is  also  a  valuable  means  of  restricting  the  contagion. 

Streptococcus  infections  like  influenza  are  at  present  most  difficult  of 
control.  We  must  be  content  to  check  by  isolation  methods  their  invasion 
of  other  respiratory  diseases.  Preeminently  in  limiting  secondary 
streptococcus  infections  the  barriers  of  cubicle  and  mask  should  be 
efficacious.  The  appearance  of  a  streptococcus  outbreak  should 
invariably  lead  to  an  investigation  of  the  milk  supply.  Whether  the  evi- 
dence of  milk  contamination  is  obtained  or  not,  pasteurization  or  boiling 
of  the  milk  and  milk  products  is  advisable.  All  influences  previously 
discussed  that  lower  the  resistance  to  infection  should  be  avoided  as  far 
as  possible,  but  they  play  a  role  in  cross  infections  of  less  importance  than 
factors  of  proximity. 


BIBLIOGRAPHY 

1.  KRAUSE,  A.  K.:  Jour.  Outdoor  Life,  1918,  XV,  i. 

2.  ROGERS,  J.  B.:  Am.  Rev.  of  Tuberculosis,  1919,  III,  X,  238. 

3.  FLUGGE,  F.:  Zeitsch.  f.  Hygiene,  1899,  XXXI,  107. 

4.  DOUST,    B.    C.,    and    LYON,    A.    B.:    Jour.    Am.    Med.    Assoc,     1918, 

LXXI,  1216. 

5.  LYNCH,  C.,  and  GUMMING,  J.  G.:  Military  Surgeon,  1918,  XLIII,  597. 

6.  SAVAGE,  W.  G.:  Milk  and  the  Public  Health.     London,  1912,  114. 

7.  ASHBY,  A.:  Public  Health,  1906-07,  XIX,  145. 

8.  MATHERS,  G.:  Jour.  Inf.  Dis.,  1916,  XIX,  222. 

9.  SMITH,  T.,  and  BROWN,  J.  H.:  Jour.  Med.  Res.,  1914-15,  XXXI,  455. 

10.  ZINSSER,  H.:  War  Medicine,  1918,  II,  316. 

11.  EMERSON,  H.:  War  Medicine,  1918,  II,  311. 

12.  COLE,  R.,  and  MacCALLUM,  W.  G.:  Jour.  Am.  Med.  Assoc,  1918,  LXX, 

1 146. 

13.  LEVY,  R.  L.,  and  ALEXANDER,  H.  C. :  Jour.  Am.  Med.  Assoc,   1918, 

LXX,  1827. 

14.  ZINGHER,  A.:  Am.  Jour.  Dis.  of  Child.,  1918,  XVI,  83. 


728     CONTROL  OF  ACUTE  RESPIRATORY  INFECTIONS 

15.  CECIL,  R.  L.,  and  AUSTIN,  R.  S.:  Quoted  by  Cecil  and  Vaughan,  loc.  cit. 

16.  CECIL,  R.  L.,  and  VAUGHAN,  H.  F.:  Jour.  Exper.  Med.,   1919,  XXIX, 

457- 

17.  ROSENOW,  E.  C:  Jour.  Am.  Med.  Assoc,  1919,  LXXII,  31. 

18.  McCOY,  G.  W.:  Public  Health  Rep.,  1919,  XXXIV,  1193. 

19.  KEEFER,  F.  R.,  FRIEDBERG,  S.  A.,  and  ARONSON,  J.  D. :  Jour.  Am. 

Med.  Assoc,  1918,  LXXI,  1206. 

20.  CHAPIN,  C.  v.:  Sources  and  Modes  of  Infection.    New  York,  1912,  217. 

21.  Gordon  Report  on  Health  of  Manchester,  1908,  1206. 

22.  STRONG,  R.,  and  TEAGUE,  O.:  Jour.  Am.  Med.  Assoc,  191 1,  LVII,  1270. 

23.  MELTZER,  S.  J.:  Med.  Rec,  1916,  XC,  292. 

24.  WEAVER,  G.  H.:  Jour.  Am.  Med.  Assoc,  1918,  LXXI,  1405. 

25.  CAPPS,  J.  A.:  Jour.  Am.  Med.  Assoc,  1918,  LXXI,  448. 

26.  HALLER,  D.  A.,  and  COLWELL,  R.  C:  Jour.  Am.  Med.  Assoc,  1918, 

LXXI,  1213. 


CHAPTER  XIX 

ENVIRONMENT  AND  ITS  RELATION  TO 
HEALTH  AND  DISEASE 

By  LEWELLYS  F.  BARKER 

Table  of  Contents 

Physical  Components  of  Environment 729 

Thermic  Influences 729 

Influence  of  Light 731 

Electrical  Influences        732 

Influences  of  X-ray  and  Radium 732 

Influence  of  Air  Pressure 733 

Influence  of  Propagated  Motion  (Kinetic  Influence) 734 

Chemical  Components  of  Environment 735 

Biological  Components  of  Environment 736 

Psychological,  Social,  Economic  and  Political  Components  of  Environment  .      .  737 

From  the  time  of  beginning  as  a  fertilized  egg-cell  to  the  time  of  death  each 
human  individual  is  subjected  to  environmental  influences  that  are  ever  chang- 
ing. The  intra-uterine,  infantile,  puerile,  adolescent,  mature  and  senescent 
periods  of  life  have,  each  of  them,  to  a  varying  degree,  certain  special  surround- 
ings that  may  be  of  significance  both  for  health  and  for  disease.  In  the  forma- 
tion of  environments,  physical,  chemical,  biological,  psychological  and  social 
components  participate  in  greatly  differing  combinations.  (Some  of  these  effects 
are  described  also  in  other  chapters;  reference  to  the  index  will  show  where 
these  descriptions  may  be  found.) 

Physical  Components  of  Environments 

Among  the  physical  influences  of  environments  are  included  those  of  tempera- 
ture, light,  electricity,  x-rays  and  radium,  air  pressure  and  propagated  motion. 

Thermic  Influences 

These  have  been  of  great  importance  in  influencing  the  development  of  human 
civilization  as  well  as  of  personal  hygiene.     The  world  man  lives  in  has  great 
Vol.  I.  933 

729 


730     ENVIRONMENT,  ITS  RELATION  TO  HEALTH  AND  DISEASE 

extremes  of  temperature;  the  mean  yearly  temperature  of  a  climate  may  be  as 
high  as  +30°  C.  or  as  low  as  -26°  C,  the  mean  monthly  temperature  as  high 
as  +39°  C.  or  as  low  as  —51°  C,  and  the  extreme  single  temperatures  may 
be  as  high  as  +56°  C.  and  as  low  as  -63°  C,  and  yet  thanks  to  the  heat- 
regulating  mechanisms  of  the  body  and  to  the  types  of  clothing  and  dwelHngs 
he  has  devised,  man  can  continue  to  exist  in  such  cUmates  for  he  creates  a  "pri- 
vate climate"  within  the  general  thermal  environment.  The  mechanisms  within 
man's  body  for  the  regulation  of  his  temperature  are  complex;  chemical  regu- 
lation with  heat  production  depends  largely  upon  (i)  muscle  contraction  (as  in 
shivering)  and  (2)  more  rapid  combustion  processes  because  of  the  increased  rate 
of  metabolism  when  the  external  temperature  falls;  physical  regulation  with  heat 
dissipation  depends  upon  the  giving  off  of  heat  to  the  surroundings  (i)  by  con- 
duction and  radiation  and  (2)  by  the  evaporation  of  secreted  sweat.  These  regu- 
latory mechanisms  are  mediated  by  vegetative  centres  in  the  hypothalamus; 
afferent  impulses  to  these  centres  are  excited  by  stimulation  of  the  warm-points 
in  the  skin  by  heat  and  of  the  cold-points  by  cold;  efferent  impulses  from  the 
same  centres  pass  to  the  muscles,  to  the  sweat  glands  and  vasomotor  apparatus 
of  the  skin,  and  to  the  structures  mediating  the  metaboHc  rate.  Though  these 
heat-regulating  mechanisms  provide  excellent  physiological  methods  of  defence 
to  changes  in  the  thermal  environment,  there  are  limits  beyond  which  they  are 
no  longer  capable  of  preventing  local  or  general  injury  to  either  heat  or  cold. 

Thus  the  local  injuries  ("burns")  from  excessive  heat  may  vary  in  degree 
from  erythema  and  blistering  to  necrosis  and  actual  charring;  if  local  burns  be 
extensive,  symptoms  of  general  intoxication  of  the  body  will  follow,  and  death 
has  occurred  as  the  result  of  a  burn  of  approximately  one-eighth  of  the  body- 
surface. 

When  the  human  body  as  a  whole  becomes  overheated,  say  because  of 
strenuous  muscular  activity  in  a  very  hot  environment,  so-called  "heat  stroke" 
may  occur  of  which  several  types  have  been  observed,  including  (i)  heat  pros- 
tration, (2)  hyperpyretic  heat  stroke  and  (3)  forms  with  gastro-intestinal  or  psy- 
chic symptoms  predominant.  In  the  Great  War  there  were  many  cases  among 
the  troops  in  Mesopotamia  and  other  hot  regions  with  a  relatively  high  mor- 
tality. But  even  in  temperate  climates,  heat  stroke  is  frequently  met  with, 
sometimes  in  "epidemics"  as  in  New  York  City  in  August  1896. 

In  "heat  stroke"  the  blood  of  the  body  as  a  whole  becomes  overheated  and 
causes  overheating  of  the  brain  centres;  in  "sun-stroke"  the  same  centres  may 
become  overheated  through  the  direct  over-heating  of  the  head. 

Excessive  cold  can  cause  local  injury  manifested  as  "frost-bite"  or  "freez- 
ing"; there  may  be  every  degree  of  injury  from  erythema  to  gangrene.  During 
the  World  War  there  were  many  cases  of  so-called  "trench  foot",  following  ex- 
posure of  the  feet  to  melting  snow  in  the  trenches.     It  was  found  this  snow 

Vol.  I.  933 


PHYSICAL  COMPONSNETS  OF  ENVIRONMENT  731 

water  withdrew  more  heat  from  the  feet  than  dry  cold  snow  did.  A  milder 
form  of  local  injury  following  exposure  of  predisposed  persons  to  cold  in  our 
climate  is  that  known  as  chilblains;  here,  however,  the  local  tissue  disposition 
is  the  most  important  factor,  cold  acting  as  a  provocative  cause. 

The  general  effects  of  low  temperatures  upon  the  body  have  been  studied 
both  in  man  and  in  experimental  animals.  In  insufficiently  protected  persons 
exposed  to  cold  winds,  cold  water,  or  snow  storms  over  too  long  a  period,  the 
temperature  of  the  interior  of  the  body  may  fall  to  so  low  a  level  that  death 
results.  Drunken  men,  Alpine  tourists  and  shipwrecked  sailors  sometimes  meet 
with  death  from  cold.  After  the  preliminary  chilling,  they  are  overpowered  by 
a  sense  of  fatigue,  begin  to  yawn,  become  drowsy  and  enter  into  coma. 

Of  late  years,  much  attention  has  been  given  to  the  "common  cold"  and  to 
the  nasal,  pharyngeal,  and  pulmonary  sequels  of  "catching  cold".  Both  laymen 
and  physicians  are  convinced  that  exposure  to  cold  and  damp  may  be  an  im- 
portant etiological  factor  in  "catching  cold",  though  disposition  (inherited  or 
acquired)  to  colds  seems  to  be  just  as  important,  and  at  least  in  many  cases 
infection  also  plays  a  part.  The  effect  of  the  cold  may  directly  injure  local 
tissues;  many,  however,  are  wedded  to  the  hypothesis  that  the  cold,  through 
reflex  action,  changes  the  blood-supply  of  certain  organs  (nose,  throat,  lungs) 
in  which  the  disease  develops.  Much  progress  has  been  made  in  lessening  the 
susceptibility  to  colds  through  wiser  methods  of  clothing,  better  ventilation  of 
houses,  practice  of  out-door  sports  and  so-called  "hardening"  measures.  Treat- 
ment of  local  infections  of  the  nose,  mouth,  throat  and  paranasal  sinuses  seems 
also  to  be  helpful  in  lessening  disposition  to  "catching  cold".  Many  persons 
have  found  by  experience  that  when  after  exposure  to  cold  they  have  observed 
the  premonitory  symptoms  of  a  cold  they  can  often  abort  it  by  provoking  sweat 
and  keeping  warm  afterwards. 

Influence  of  Light 

Sunlight,  if  allowed  to  act  upon  the  skin,  may  cause  erythema  and  dermatitis. 
The  erythema  produced  may  occur  at  once  or  shortly  after  exposure  and  dis- 
appear again  in  a  few  hours;  this  type  is  like  any  burn  due  simply  to  the  heat 
action  of  the  light  rays  and  the  ultra  red  rays.  Another  type  of  erythema,  the 
so-called  "photochemical  exanthem",  appears  only  after  a  latent  period  of 
several  hours  and  is  due  to  the  action  of  the  ultraviolet  rays;  this  type  is  often 
met  with  among  tourists  in  the  high  mountains  and  upon  glaciers,  since  the 
sunlight  at  high  altitudes  is  said  to  contain  relatively  more  ultraviolet  rays  than 
the  light  at  lower  levels.  The  pigmentation  that  follows  the  dermatitis  is  an 
especial  protection  against  the  skin-harming  effects  of  ultraviolet  rays.  It  is 
said  that  the  application  of  a  5  per  cent,  quinine  paste  to  the  exposed  parts  of 

Vol.  I.  933 


732      ENVIRONMENT,   ITS   RELATION  TO  HEALTH  AND   DISEASE 

the  skin,  when  making  a  mountain  or  glacier  tour,  will  protect  from  injury  to 
the  skin  since  this  paste  will  absorb  most  of  the  ultraviolet  rays. 

Electrical  Influences 

About  electrical  influences  in  the  environment  aside  from  Hghtning  stroke 
and  accidental  contact  with  strong  electrical  currents  but  Httle  is  known. 
Death  due  to  being  struck  by  lightning  has  decreased  in  houses,  since  lightning 
rods  have  been  in  use,  but  there  has  been  but  little  if  any  change  in  the  number 
struck  in  the  open.  Some  five  hundred  persons  yearly  die  from  this  cause  in 
the  United  States. 

With  the  great  increase  in  the  use  of  electricity  in  industrial  establishments 
and  in  households,  accidental  contacts  with  powerful  electric  currents  have  be- 
come ever  more  common,  so  that  now  approximately  ten  persons  per  million  of 
population  are  killed  by  such  contacts  each  year  in  the  United  States.  The 
majority  of  these  accidents,  though  not  all,  have  been  due  to  contact  with 
alternating  currents.  In  case  of  contact,  a  person  standing  in  rooms  with  dry 
floors,  carpets  or  Hnoleum  is  safer  than  one  standing  in  rooms  with  tiled,  brick 
or  cement  floors.  Many  safety  devices  have  been  introduced  that  lessen  the 
likelihood  of  electrical  injury. 

When  a  strong  current  enters  the  human  body,  violent  muscular  contractions 
occur.  It  is  fortunate  when  such  contractions  remove  the  part,  at  which  the 
current  has  entered,  from  contact  with  the  conductor  of  the  current.  Sometimes, 
when  the  part  entered  is  the  hand,  there  is  tetanic  contraction  of  the  muscles 
so  that  the  conductor  is  firmly  gripped  and  cannot  be  let  go.  On  lightning 
stroke,  the  person  struck  may  faU  dead,  or  apparently  dead,  or  he  may  cry  out 
before  losing  consciousness. 

When  the  current  has  not  been  too  strong,  death  does  not  occur;  even  coma- 
tose patients  may  be  revived,  especially  with  artificial  respiration.  On  recovery, 
evidences  of  the  site  of  entry  and  of  exit  of  the  current  may  be  seen  on  the  skin 
(burns,  epidermolysis,  localized  oedema,  "Hghtning  figures",  necroses).  Some 
patients  after  injury  become  hysterical  or  show  other  evidences  of  traumatic 
neurosis.  Occasionally,  there  are  sequels  in  the  form  of  neuritis  or  of  focal 
lesions  within  the  central  nervous  system. 

Influences  of  X-Rays  and  Radium 

Roentgen  rays  and  the  gamma  rays  of  radium  have  great  capacity  for  pene- 
trating the  body  because  of  their  extremely  short  wave-lengths.     The  tissues 
of  the  body  vary  in  their  sensibility  to  the  action  of  the  rays,  the  lymphadenoid 
tissues  and  the  gonadal  tissues  being  perhaps  most  sensitive,  the  connective 
Vol.  I.  933 


PHYSICAL  COMPONENTS  OF  ENVIRONMENT  733 

tissues,  cartilage  and  bone  least  sensitive.  Mild  exposures,  not  too  often  re- 
peated, appear  to  be  harmless,  whereas  stronger  and  frequent  exposures  can 
cause  severe  damage,  even  death,  of  tissue  cells. 

Because  of  the  sensitiveness  of  the  skin,  radiologists  are  careful  in  examining 
patients  and  especially  when  treating  them  with  larger  dosage  to  avoid  the 
production  of  a  dermatitis;  hence  at  any  one  treatment  a  single  area  receives 
only  a  certain  fraction  of  a  "skin-erythema  dose".  Chronic  dermatitis,  with 
hyperkeratoses  and  changes  in  the  finger  nails,  frequently  develops  among 
x-ray  operators  and  should  be  avoided  by  better  protective  measures  than  those 
formerly  used;  all  too  many  of  our  pioneer  roentgenologists  have  succumbed  to 
carcinomatous  processes  that  developed  upon  the  basis  of  skin  injuries  due  to 
the  x-rays. 

With  the  increased  use  of  radium  and  of  x-rays  for  the  treatment  of  leu- 
kaemias, hyperthyroidism  and  neoplasms,  physicians  have  become  ever  better 
acquainted  with  the  dangers  of  excessive  dosage  and  have  formulated  rules  of 
safety.  The  incautious  application  of  these  rays  during  pregnancy  may  cause 
abortion,  or  may  injure  the  foetus  if  it  survive. 

Influence  of  Air-Pressure 

Many  persons  are  sensitive  to  changes  in  the  weather.  Though  these  changes 
are  associated  with  rise  or  fall  of  the  barometer,  it  is  not  believed  that  it  is  the 
mere  oscillations  in  the  air  pressure  that  are  directly  responsible  for  the  weather 
sensitiveness  complained  of.  It  is,  apparently,  only  in  very  rarefied  air  or  very 
highly  compressed  air  that  the  changes  in  pressure  cause  functional  distur- 
bances. 

When  the  body  is  exposed  to  very  high  pressures,  disturbing  symptoms, 
aside  from  those  referable  to  the  ears  and  paranasal  sinuses,  rarely  occur  unless 
there  is  too  sudden  diminution  of  the  pressure.  Bridge  builders  who  work  in 
large  water-tight  and  air-tight  cases,  caissons,  in  laying  foundations  in  deep 
water  run  the  risk  of  developing  "caisson  disease",  unless  great  care  is  taken  to 
return  only  gradually  to  normal  atmospheric  pressures.  They  are  prone  to 
suffer  from  pains  in  the  abdomen  and  in  the  joints  of  the  extremities,  "the 
bends",  from  pruritus,  epistaxis  and  vomiting.  In  some  instances,  severer  syn- 
dromes, spastic  paraplegia,  a  Meniere  syndrome,  make  their  appearance; 
occasionally,  especially  if  circulatory  or  pulmonary  disease  have  pre-existed,  fa- 
talities occur. 

The  phenomena  are  explained  through  the  fact  that  nitrogen  is  absorbed  by 
the  fluids  and  tissues  of  the  body  when  the  worker  is  exposed  to  high  pressure, 
and  when  these  are  reduced  too  rapidly,  nitrogen  gas  bubbles  develop  in  the 
tissue  spaces  and  in  the  blood  and  injure  tissue  elements  by  the  pressure  they 

Vol.  I.  933 


734     ENVIRONMENT,   ITS  RELATION  TO  HEALTH  AND   DISEASE 

exert,  or  cause  gas  embolism  of  smaller  vessels  with  resulting  local  ischaemias. 
That  is  why  laws  have  been  passed  requiring  slow  decompression,  and  by  suc- 
cessive stages,  of  the  workers. 

The  danger  to  deep  water  divers,  who  encased  in  water-tight  and  air-tight 
diving  suits  have  to  stay  at  times  under  pressures  from  five  to  seven  times  the 
normal  atmospheric  pressure,  is  still  greater  because  of  the  difficulty  or  im- 
possibility of  providing  for  slow  decompression.  Prophylaxis  here  consists  in 
shortening  the  period  of  exposure  to  high  pressure  in  order  that  the  body  tissues 
and  fluids  do  not  absorb  so  much  nitrogen. 

When  the  body  is  exposed  to  very  low  pressures,  the  diminished  partial  pres- 
sure of  oxygen  makes  itself  felt;  dyspnoea  and  cyanosis  develop  especially  in 
those  not  trained,  "acclimatized",  to  life  at  low  pressures.  Thus  arise  moun- 
tain-sickness among  climbers,  balloon  sickness  and  aviators'  sickness  at  high 
altitudes;  some  of  the  latter  provide  themselves  with  oxygen  masks  for  prophy- 
lactic purposes. 

The  influences  of  weather  and  of  climate  in  general  depend  largely  upon  phys- 
ical components  of  environment.  Thus,  studies  of  the  relationships  of  tuber- 
culosis to  the  environment  have  indicated  that  hot  climates,  low  altitudes  and 
moist  atmospheres  are,  in  general,  more  unfavorable  than  their  opposites. 

Influence  of  Propagated  Motion  {Kinetic  Influences) 

Sudden  acceleration  of  motion  in  any  direction  by  irritation  of  the  vestibular 
apparatus  can  cause  dizziness  and  nausea,  to  which  rapidly  changing  optical 
impressions  may  also  contribute.  Personal  disposition  plays  a  great  role,  some 
people  being  very  sensitive,  others  very  resistant  to  the  influences  of  changes  of 
propagated  motion.  Sea-sickness  is  the  best  example  of  a  "kinetosis";  "car- 
sickness"  and  "elevator-sickness"  are  minor  forms.  In  the  production  of  sea- 
sickness, except  in  the  cases  due  to  auto-suggestion,  the  pitch  of  a  boat  is  more 
effective  than  the  roll,  though  worst  of  all  is  the  combined  pitch  and  roll  spoken 
of  as  "cork-screw-like  motion".  Susceptibihty  to  sea-sickness  is  said  to  be 
absent  in  children  under  two  years  of  age  and  only  slight  up  to  the  sixth  or 
eighth  year  of  life.  A  few  adults,  perhaps  3  per  cent.,  appear  to  be  almost 
wholly  immune  to  sea-sickness,  but  many,  who  have  thought  themselves  im- 
mune, have  found  in  extraordinary  circumstances  that  they  were  really  not  so. 
Visceroptosis  seems  to  be  a  predisposing  factor.  Many  do  not  become  ill,  if 
they  stay  on  deck  in  the  open  air,  whereas  in  badly  ventilated  rooms  they 
quickly  succumb.  Mild  sedatives  like  phenobarbital  or  sodium  bromide  by 
lessening  the  sensitivity  of  the  nerve  centres  are  used  by  some  as  preventatives. 

It  is  interesting  that  Bohec  has  reported  that  sailors  with  inborn  or  acquired 
immunity    to   sea-sickness    sometimes   develop    "land-sickness"    or    "channel 

Vol.  I.  933 


CHEMICAL  COMPONENTS  OF  ENVIRONMENT  735 

sickness"  when  at  or  near  the  end  of  a  voyage!  Though  they  do  not  have 
vertigo,  they  may  complain  of  headache,  feelings  of  anxiety,  anorexia,  nausea 
and  insomnia,  to  be  followed  later  by  great  drowsiness. 

Chemical  Components  of  Environment 

Man  lives  in  a  chemical  as  well  as  a  physical  environment.  Thus,  in  the 
open  air,  he  is  constantly  inhaling  oxygen,  nitrogen,  and  other  gases  and  par- 
ticles, dusts  of  various  sorts;  and  in  houses  and  in  industrial  establishments  the 
air  may  be  contaminated  by  many  different  gaseous  substances,  some  of  which 
may  be  toxic  to  the  respiratory  passages,  occasionally  to  the  skin,  and  often, 
after  absorption,  to  the  organism  as  a  whole  by  way  of  the  blood. 

Again,  in  food  and  drink,  a  vast  number  of  chemical  substances  are  ingested, 
most  of  them  beneficial,  some  of  them  harmful  when  ingested  in  excessive 
quantities,  or  when  food-stuffs  have  been  improperly  preserved  or  prepared. 

In  addition,  human  beings  may,  in  certain  environmental  circumstances,  be 
exposed  to  the  action  of  chemical  substances  that  through  their  chemical  ef- 
fects may  provoke  injury  or  disease,  or  even  cause  death.  Such  "poisons" 
may  do  harm  by  the  local  effects  they  produce  upon  the  skin  or  mucous  mem- 
branes by  virtue  of  their  concentration  and  their  physico-chemical  properties 
or  through  their  general  effects  upon  the  bodily  organs  after  absorption  into  the 
blood. 

The  amounts  of  chemical  substances  that  act  upon  the  body  are  very  impor- 
tant from  the  standpoint  of  toxic  injury.  Thus  very  minute  amounts  of  certain 
substances  (like  alkaloids,  arsenic,  or  potassium  cyanide)  may  be  very  harmful 
or  fatal;  doses  of  from  5  to  50  g.  of  potassium  chlorate  or  potassium  nitrate 
may  kill;  even  ordinary  foodstuffs  may  be  toxic  in  large  doses  for  we  read  in 
the  literature  even  of  "water-intoxication",  and  a  favorite  method  of  com- 
mitting suicide  among  the  Chinese  has  been  to  swallow  large  quantities  of 
common  salt  (300  to  500  g.).  It  should  be  borne  in  mind,  too,  that  certain 
persons  may  show  outspoken  symptoms  after  ingestion  of  much  smaller  amounts 
of  certain  chemical  substances  than  those  that  are  innocuous  to  the  majority  of 
people,  owing  to  excessive  sensitivity  or  so-called  "  idiosyncracy " ;  in  this  con- 
nexion, we  have  in  recent  years  become  familiar  with  a  whole  series  of  "allergic 
reactions"  (see  chapters  on  hay  fever,  asthma,  and  serum  disease). 

Toxic  amounts  of  chemical  substances  may  reach  human  beings  either  through 
ignorance,  mistake,  or  intention.  Thus,  industrial  workers  may  be  subject  to 
chronic  poisoning  inadvertently,  neither  they  nor  their  employers  being  aware 
that  dangers  exist.  Many  persons  become  gradually  addicted  to  the  excessive 
use  of  alcohol,  tobacco,  coffee  or  tea,  or  to  the  morphine,  cocaine,  barbital  or 
sodium  amytal  habit,  scarcely  realizing  what  they  are  drifting  into.    Physicians, 

Vol.  I.  933 


736     ENVIRONMENT,   ITS   RELATION  TO  HEALTH  AND   DISEASE 

pharmacists  and  nurses  or  their  aids  occasionally  administer  poisonous  substances 
entirely  by  mistake.  Criminals  use  poisons  with  murderous  aims.  Suicides  are 
often  due  to  either  impulsive  or  deliberate  self-poisoning. 

Some  poisons  in  small  doses  produce  no  evident  immediate  effects,  but  long 
continued  exposure  to  them  may  result  in  slow  changes  in  the  body  and  give 
rise  later  on  to  symptoms  or  increase  susceptibility  to  disease.  Thus,  persons 
exposed  to  benzol  fumes  may  after  weeks  or  months  give  rise  to  a  progressive 
anaemia  and  to  a  hemorrhagic  tendency.  In  factories  for  the  manufacture  of 
artificial  silk  and  among  certain  varnish  workers  poisonings  by  organic  chlorine 
preparations  may  lead  to  atrophy  of  the  liver  and  to  disturbances  of  the  hver 
functions.  The  prophylaxis  of  acute  and  chronic  intoxications  has  become,  in  re- 
cent years,  one  of  the  most  important  tasks  of  preventive  medicine.  In  other 
parts  of  this  treatise,  the  toxicology  of  the  many  inorganic  poisons  and  of  the 
organic  poisons  of  industrial,  plant  and  animal  origin  is  discussed. 

Biological  Components  of  Environment 

Human  beings  are  surrounded  not  only  by  other  persons  but  also  by  a  host  of 
other  living  organisms,  many  of  them  most  helpful,  others  often  highly  detri- 
mental. To  these  biological  components  of  man's  environment  ever-increasing 
attention  is  being  paid.  Among  the  harmful  members  are  certain  of  the  bac- 
teria, the  ultra-filtrable  viruses  and  the  animal  parasites. 

Bacteria  often  cause  intoxications  through  baneful  alterations  of  food-stuffs; 
meat-poisonings,  botulism,  poisoning  through  fish,  molluscs  and  Crustacea,  and 
intoxications  from  milk,  cheese,  eggs,  potatoes  and  preserved  foods  of  various 
sorts  are  notable  examples. 

The  members  of  the  great  group  of  acute  and  chronic  infectious  diseases  are, 
in  large  part,  caused  by  bacterial  and  protozoan  invaders  of  man  from  his  sur- 
roundings; some  are  due  definitely  to  ultra-filtrable  viruses;  some,  again,  are  of 
unknown  etiology  but  presumably  are  due  to  as  yet  undiscovered  living  in- 
fectious agents  of  some  sort. 

The  proof  that  diphtheria,  tetanus,  epidemic  cerebrospinal  meningitis, 
cholera,  bacillary  dysentery,  typhoid  fever,  typhus  fever,  erysipelas,  the  septic 
diseases,  tuberculosis,  leprosy,  plague,  undulant  fever,  tularaemia,  gonorrhoea 
and  syphilis  are  due  to  cocci,  bacilli  or  spirochaetes  is  one  of  the  great  triumphs 
of  modern  medicine.  Malaria  has  been  shown  to  be  due  to  a  protozoan  parasite 
introduced  by  the  bite  of  a  special  mosquito,  and  yellow  fever  is  due  to  a  living 
virus  introduced  by  another  type  of  mosquito.  Acute  anterior  poliomyelitis 
and  epidemic  encephalitis  have  been  proven  to  be  due  to  invasions  by  neuro- 
tropic ultra-filtrable  viruses.  The  etiological  agents  of  many  infectious  diseases, 
among  them  the  acute  exanthemata,  remain  still  to  be  discovered. 

Vol.  I.  933 


PSYCHOLOGICAL,  SOCL\L  AND    OTHER  COMPONENTS       737 

Psychological,   Social,   Economic  and  Political 
Components  of  Environment 

The  influence  of  psychological  components  of  environments  has  received  an 
increasing  amount  of  attention  during  the  past  few  decades.  It  has  become  ever 
more  clear  that  the  tendency  of  the  layman  to  attribute  mental  disturbances  to 
psychic  traumata  of  various  sorts  is  due  in  large  part  to  a  confusion  of  cause 
and  effect.  In  the  so-called  "reactive  melancholia"  especially,  the  inherited 
tendency  to  depression  is  often  of  greater  importance  than  the  psychic  influence 
from  without  to  which  it  may  be  attributed.  In  Freud's  theory  of  the  origin  of 
the  psychoneuroses  and  some  psychoses  the  "suppressed  complexes"  may  have 
played  a  part  in  altering  constitutional  make-up  so  that  in  later  life  there  is  an 
abnormal  readiness  to  react  to  psychic  influences  in  a  pathological  way.  Thus, 
hysterical  manifestations  are  believed  by  many  to  be  of  psychogenic  origin,  in 
that  certain  persons  expect  to  be  ill  in  a  certain  way,  or  desire  to  appear  to 
have  a  certain  form  of  ailment;  in  conflicts,  or  in  certain  situations,  they  tend 
to  "react"  in  a  characteristic  way.  But,  recently,  psychiatrists  seem  inclined 
to  accept  the  view  that  the  abnormal  mental  pictures  they  see  in  the  neuroses 
and  psychoses  that  develop  after  strong  psychic  influences  in  the  environment, 
such  as  in  earthquakes,  war,  social  upheavals,  etc.,  depend  more  upon  the  per- 
sonality make-up  of  the  individuals  concerned  than  upon  the  particular  form  of 
the  external  irritation. 

Medical  literature  is  full  of  reports  of  cases  in  which  the  psychic  influences 
attendant  upon  earthquakes,  shipwrecks,  strikes,  panics,  explosions,  fires,  rail- 
way and  motor  accidents,  economic  crises,  political  upheavals  and  great  religious 
movements  have  been  regarded  as  precipitating  causes  of  emotional  upsets  and 
of  the  insanities  of  various  sorts.  The  psychic  effects  of  homesickness,  of 
estrangements,  of  isolation,  of  imprisonment,  of  legal  entanglements,  of  con- 
flicts in  familial  and  social  life,  of  spiritualistic  seances  and  other  special  situa- 
tions have  been  much  commented  upon.  But  writers  have  had  great  difficulty 
in  determining  in  how  far  in  any  given  case  the  psychic  influences  were  respon- 
sible, and  in  how  far  the  anlage  has  been  responsible.  Experiences  in  the  Great 
War,  especially,  proved  how  dangerous  it  is  to  speak  of  pure  psychic  causal 
stimuli.  To  the  surprise  of  everybody,  it  was  found  that  the  frightful  condi- 
tions experienced,  the  horrible  spectacles  witnessed  and  the  fears  of  injury  or 
death  that  could  not  help  but  exist  gave  rise  to  far  less  psychopathic  reaction 
than  many  had  anticipated;  indeed,  not  a  few  persons  who  before  the  war  had 
manifested  hypochondriacal  and  psychasthenic  symptoms  got  rid  of  them  instead 
of  finding  them  increased!  And  since  the  war,  some  doubt  has  become  preva- 
lent regarding  the  etiological  influence  of  fear  in  the  production  of  the  so-called 
"fright-psychoses".     An  analysis  of  many  of  them  has  made  it  clear  that  pre- 

VOL.  I.    933 


738     ENVIRONMENT,   ITS   RELATION  TO  HEALTH  AND   DISEASE 

existent  states  of  somatic  weakness  on  the  one  hand,  or  pre-existent  desires  of 
hysterical  persons  on  the  other,  or  mixtures  of  the  two  were  largely  responsible 
for  the  development  of  the  profound  feeling  of  physical  and  psychical  impotence 
of  those  who  manifested  acute  mental  disturbances  after  emotional  shocks  in 
the  war.  Many  of  those  who  were  affected  were  of  hyperthyroid  tendency  or 
had  exhibited  vasomotor  instability  earlier. 

Much  has  been  written  also  about  the  "exhaustion-syndromes"  or  "fatigue 
syndromes"  of  the  war,  occurring  after  prolonged  physical,  intellectual  or 
emotional  strains.  Even  persons  previously  healthy  might  after  such  excessive 
fatigue  enter  a  state  of  extreme  lassitude  accompanied  by  feelings  of  complete 
indifference,  apathy  or  morose  depression.  During  such  fatigue-states,  illusions 
and  hallucinations  were  sometimes  observed.  The  mechanical  excitability  of  the 
muscles  was  increased,  the  pulse-rate  became  accelerated,  the  blood  pressure 
sometimes  rose,  and  there  was  a  tendency  to  sweating  and  to  paraesthesias. 
These  otherwise  healthy  persons  usually  recovered  completely,  if  they  were  able 
to  secure  a  long  period  of  sleep.  A  most  striking  thing  during  the  war  was  the 
extraordinary  capacity  of  the  healthy  brain  to  resist  the  deleterious  influences 
of  severe  exhaustion  combined  with  strong  excitation  of  the  emotions,  often  too 
with  severe  bodily  injuries.  In  less  healthy  brains,  exhaustion  psychoses  often 
appeared.  Moreover,  under  the  influence  of  great  fatigue  epilepsies  sometimes 
developed  and  latent  neurosyphilis  or  latent  dementia  paralytica  tended  to  be- 
come manifest. 

Recently,  there  has  been  ample  opportunity  to  observe  the  mode  of  reaction 
of  people  both  in  Europe  and  in  America  to  a  most  severe  economic  crisis. 
More  astonishing  perhaps  than  the  suicides  and  the  depressions  reported  has 
been  the  calmness  and  the  brave  willingness  to  adjust  to  the  difficulties  of  the 
time;    it  has  become  in  many  circles  "bad  form"  to  complain. 

In  Russia,  during  the  past  decade,  the  influence  of  rapidly  changing  forms  of 
social  and  political  organization  could  be  witnessed;  in  Italy  the  influence  of 
fascism  and  in  Germany  and  Austria,  the  influence  of  the  change  from  a  mo- 
narchical government  to  a  republican  form  has  been  in  evidence.  In  time,  doubt- 
less, we  shall  have  reports  of  systematic  studies  of  the  effects  of  such  influences. 

Since  the  opening  of  the  new  century,  the  mental  hygiene  movement  has 
developed  rapidly,  and  the  public  has  been  ever  better  educated  in  the  mental 
hygiene  of  childhood,  of  school  life  and  of  adulthood.  It  is  hoped  that  through 
these  mental  influences,  and  especially  through  the  early  conditioning  of  reflexes 
and  the  establishment  of  desirable  behaviour  patterns,  much  may  be  accomplished 
for  general  welfare. 

July  I,  1933. 


Vol.  T.  933 


CHAPTER  XX 

MEDICAL-SOCIAL  SERVICE  AS  A  FACTOR  IN  THE 
DIAGNOSIS  AND  TREATMENT  OF  DISEASE 

By  RICHARD  C.  CABOT 


Both  in  the  causation  and  the  relief  of  disease,  bacteria  and  their 
products,  together  with  certain  physical  and  chemical  agents,  play  the 
chief  parts.  But  they  are  not  the  whole.  Psychological;  industrial,  and 
educational  factors,  for  instance,  are  also  of  some  importance.  Medical- 
social  service,  a  branch  of  social  work  in  general,  deals  with  these 
factors  and  is  therefore  a  useful  tool  in  the  medical  kit. 

In  war  medicine,  these  factors  are  at  their  minimum  and  medical- 
social  service  is  relatively  unimportant  there.  On  the  other  hand,  in 
the  hospitals  of  great  cities,  especially  in  Out-Patient  work,  the  social, 
economic,  racial,  domestic,  and  other  influences  dealt  with  by  medical- 
social  workers  are  at  their  maximum.  Hence  good  medical  practice  is 
there  impossible,  or  at  least  improbable,  without  the  social  worker's  aid. 

In  private  practice  and  especially  in  the  general  practice  of  country 
districts  and  small  towns,  the  successful  doctor  usually  does  the  social 
work  himself.  He  deals  as  best  he  can  with  the  mental,  emotional, 
and  industrial  life  of  his  patients  in  its  bearings  on  their  diseases.  He 
is  his  own  social  worker  as  he  is  his  own  surgeon,  laboratory  man, 
and  radiologist.  This  is  possible  because  he  knows  each  patient  (and 
often  his  family)  individually.  He  can  see  how  each  sufferer's  maladies 
are  the  joint  product  of  physical,  chemical,  and  bacterial  agencies  and 
of  the  worries,  deprivations,  work  conditions,  and  home  conditions 
under  which  he  lives. 

But  in  the  organized  medical  work  of  a  great  hospital  or  a  metro- 
politan public  school  it  is  impossible  for  the  physician  to  know  all  the 
important  facts  about  his  patient,  unless  those  facts  lie  on  the  surface. 
The  cut  finger,  the  diphtheritic  membrane,  the  gonorrheal  discharge  he 
can  see,  but  the  root  causes  of  the  stomach  troubles,  backaches,  debili- 
tated states  which  bring  nearly  half  the  patients  to  the  hospital  he  cannot 
see  at  once  and  has  neither  the  time  nor  the  means  to  investigate  thor- 

739 


740  MEDICAL-SOCIAL  SERVICE 

oughly.  Yet  without  finding  root  causes,  his  treatment  is  bound  to  be 
a  failure  and  his  daily  work  a  waste  of  time. 

Whenever  a  person's  sickness  arises  out  of  the  way  he  lives  (rather 
than  out  of  some  acute  catastrophe  like  an  explosion  or  a  railway 
accident),  the  doctor  must  know  how  he  lives.  But  in  hospitals  or 
public  schools  the  doctor  has  no  chance  to  grasp  these  essential  factors. 
Hence  the  need  of  such  help  as  a  good  social  worker  can  give. 

A  child  is  pale,  thin,  listless  in  school  work.  Physical  examination 
may  show  no  clues  for  diagnosis.  Questioning  seldom  helps.  But  a 
series  of  home  visits  by  a  woman  who  has  the  faculty  of  getting  along 
pleasantly  with  school  children  and  their  families,  who  can  investigate 
the  details  of  diet,  sleeping  rooms  and  sleeping  habits,  the  opportunities 
for  contagion,  the  possible  bearings  of  family  income,  family  discord 
or  paternal  alcoholism  on  the  children's  health, — this,  I  say,  may  bring 
to  light  the  facts  on  which  rational  diagnosis  and  treatment  can  be 
based. 

So  far  I  have  written  of  social  work  chiefly  in  diagnosis  and  in 
etiology  as  a  part  of  diagnosis.  But  social  work  bears  also  on  prognosis 
and  on  treatment.  If  malnutrition,  dyspepsia,  headaches,  gonorrheal 
vulvovaginitis,  scabies,  or  rheumatism  are  based  on  home  conditions 
which  we  are  practically  powerless  to  change,  then  the  prognosis  is 
a  blind  alley,  no  thoroughfare,  and  we  can  turn  our  energies  elsewhere. 

If,  on  the  other  hand,  the  causative  conditions  can  be  changed  by 
social-service  work,  then  that  is  the  treatment  indicated.  Sometimes 
really  brilliant  therapeutics  can  be  thus  achieved. 


II 

I  have  already  tried  to  show,  as  under  a  low  power  of  the  micro- 
scope, the  field  of  medical-social  work  and  the  tools  likely  to  be  useful 
there.     Seen  in  more  detail,  its  place  and  methods  are  as  follows : 

In  the  neurological  and  psychiatric  clinics  of  a  hospital  Out-Patient 
Department  and  in  the  pediatric  clinic,  almost  every  case  needs  study 
and  treatment  by  a  social  worker  acting  under  direction  of  the  Clinic 
Chief.  To  feed  babies,  to  get  older  children  properly  nourished  and 
fit  to  resist  the  common  infections  with  success,  is  a  matter  of  multi- 
tudinous detail.  An  exact  knowledge  of  how  the  child  lives,  eats, 
sleeps,  works,  and  plays  is  essential.  The  doctor  cannot  get  this  knowl- 
edge satisfactorily  by  questioning  the  child  or  its  mother.  Still  less 
can  he  be  sure  that  his  directions  and  prescriptions  are  carried  out 
exactly  and  persistently.  He  is  at  arm's  length  from  his  case.  He 
cannot  handle  it.     The  social  worker,  acting  as  his  agent  both  in  the 


MEDICAL-SOCIAL  SERVICE  741 

clinic  and  in  the  child's  home,  can  see  what  is  going  on  and  can  get 
things  done — or  at  least  ascertain  that  they  are  not  done  and  that  no 
good  results  can  therefore  be  looked  for. 

In  the  neurological  clinic  the  hemiplegics,  arteriosclerotics,  paretics, 
and  epileptics  must  be  gotten  into  institutions  or  their  home  com- 
panions must  be  shown  the  little  that  can  be  done  to  ease  and  cheer 
their  lives.  By  teaching  and  occupation  the  social  worker  can  save 
them  much  suffering,  though  medicine  and  surgery  are  practically 
helpless. 

The  "  functional  "  cases,  the  tics,  stammerers,  psychoneurotics  need 
re-education  of  a  type  which  no  clinic  physician  has  time  and  few  have 
ability  to  give.  A  properly  trained  social  worker,  by  intensive  effort, 
can  do  wonders  for  a  few  patients  and  accomplish  substantial  good  for 
many  more. 

Still  more  important  is  the  social  worker  as  a  magnet  or  focal  point 
to  which  are  drawn  the  functional  neuroses  usually  hidden  in  the 
gynecological  or  general  medical  clinics  where  they  are  maltreated  under 
diagnoses  like  gastritis,  constipation,  ptosis  (gastric,  intestinal,  or 
uterine),  endometritis,  "  anemia,"  and  debility.  In  the  orthopedic,  in  the 
general  medical  clinic,  and  in  the  departments  of  dermatology,  syphilis, 
and  tuberculosis,  social-service  work  is  important  but  somewhat  less 
essential  than  in  pediatrics  and  neurology. 

In  the  surgical  and  throat  departments  there  is  still  less  need  of 
anything  beyond  what  doctors  and  nurses  can  give. 


Ill 

What  the  social  worker  does  for  disease  can  be  grouped  under  four 
headings:  (a)  Discovery,  (b)  prevention,  (c)  education,  (d)  dis- 
position. 

The  discovery  of  concealed  nests,  foci,  or  cases  of  disease  through 
visits  to  the  patient's  home,  workshop,  or  school,  can  be  carried  out 
by  health  officers  or  public  health  nurses  as  well  as  by  social  workers, 
especially  when  the  data  sought  for  are  obvious.  Thus  hidden  nests 
of  malaria,  uncinariasis,  pellagra,  lead  poisoning,  and  tuberculosis  are 
now  and  then  brought  to  light  by  public  officials. 

But  in  hospital  work  where  the  single  case  of  phthisis,  rickets, 
syphilis,  or  occupational  disease  is  the  natural  starting-point  and  spur 
to  the  search  for  nests  of  cases  like  it,  we  need  someone  who  can  act 
as  the  doctor's  and  the  hospital's  agent,  following  a  clue  held  there. 
Because  the  social  worker  is  not  a  public  official  and  comes  from  an 
institution  which  tries  to  assist  rather  than  to  discipline  or  check  people. 


742  MEDICAL-SOCIAL  SERVICE 

she  *  is  in  a  good  position  psychologically  to  get  the  facts  she  is  after. 
She  is  welcome.  People  are  not  afraid  of  her  and  are  less  likely  to 
lie  to  her  than  to  a  public  health  official. 

Besides  the  discovery  of  new  cases  of  disease,  the  social  worker, 
by  her  greater  intimacy  with  the  patient's  family  and  by  her  chance  to 
talk  with  him  uninterrupted  in  his  home  and  for  a  good  while,  may 
find  nezu  features  in  the  cases  already  known  and  treated.  Omissions 
in  the  history,  new  light  on  its  interpretation,  further  links  in  the  chain 
of  causation  may  be  brought  out  thus.  Why  cannot  the  doctor  do  this 
better?  First,  because  under  present  conditions  of  hospital  organiza- 
tion he  has  not  the  time  for  home  visits;  i.e.  he  is  more  useful  to  more 
people  by  spending  his  time  on  such  diagnoses  and  treatments  as  he 
can  offer  in  conjunction  with  the  other  elements  of  the  hospital  team- 
consultants,  assistants,  machines,  and  laboratories.  This  ties  him 
down. 

Moreover,  he  is  not  usually  an  expert  in  the  give  and  take  of  intimate 
personal  intercourse  with  people  of  the  type  who  consult  him  at  a  free 
hospital.  He  cannot  get  at  them  as  well,  understand  them  as  quickly 
or  as  far  as  a  well-trained  and  sympathetic  woman  can. 

Prevention  through  social  worker's  efforts  springs  from  the  dis- 
covery of  incipient  cases  on  home  visits  and  through  the  detailed, 
hygienic  explanations  and  therapeutic  teaching  presently  to  be  referred 
to.  She  may  thus  prevent  the  relapses  of  mental  disease,  of  peptic 
ulcer,  of  flat-foot,  of  industrial  dermatitis,  and  to  this  extent  prevent 
the  existence  of  new  cases  of  disease  of  "  old  "  patients. 

Education  in  the  details  of  diet,  sleeping  arrangements,  exercise, 
recreation,  and  the  other  departments  of  hygiene  must  be  fitted  to  the 
individual  like  a  suit  of  clothes  if  it  is  to  be  of  use  to  him.  General 
rules  are  of  little  value,  especially  if  presented  in  printed  circulars  and 
in  a  hasty  offhand  way.  The  rules  must  be  applied,  reshaped,  and 
modified  to  suit  the  individual's  needs  after  these  needs  have  been 
studied  with  care.  Moreover,  since  these  hygienic  rules  often  call  for 
the  reform  of  tough  old  habit,  one  must  use  every  effort  to  get  a 
dynamic  sufficient  to  make  the  patient  put  himself  to  so  much  trouble. 
The  fear  of  disease  and  the  doctor's  authority  can  accomplish  some- 
thing towards  making  a  man  change  his  habits  of  diet,  of  work,  or 
of  thought.  But  usually  we  need  also  the  persuasive  force  of  someone 
who  cares  for  the  individual  sufferer  and  is  believed  by  him  to  under- 
stand his  circumstances,  his  difficulties,  and  his  point  of  view.  The 
medical-social  worker,  acting  for  the  doctor  and  transmitting  his 
authority  and  his  directions  to  a  patient  who  believes  that  she  under- 

♦Why  a  woman  is  preferable  I  will  try  to  show  later. 


MEDICAL-SOCIAL  SERVICE  743 

stands  him  and  feels  a  genuine  interest  in  him,  can  accomplish  more 
therapeutic  education  than  anyone  else  now  in  sight. 

By  the  disposition  of  patients  I  mean  here  the  process  of  getting 
them  into  institutions,  of  getting  financial  or  other  aid  for  them  through 
cooperation  with  other  charitable  agencies  or  with  private  individuals; 
all  of  these  which  are  available  in  her  district  the  social  worker  first 
lists  and  sizes  up,  then  learns  to  use. 

Hospitals,  special  and  general,  sanitoria,  convalescent  homes,  homes 
for  the  aged,  special  funds  for  vacations,  for  recreation,  for  pure  milk, 
for  trade  training  (as  in  the  case  of  mutilated  persons),  exemplify  the 
tools  which  the  social  worker  learns  to  use  more  or  less  effectively  for 
hospital  patients. 

IV 

The  social-service  department  of  a  hospital  should  function  as  the 
X-ray  department  does — not  as  an  independent  agent,  but  as  part  of 
a  team  under  the  direction  of  one  guiding  mind.  The  facts  elicited  by 
the  social  worker's  studies,  talks,  and  visits  should  (like  X-ray  data) 
be  pooled  with  the  data  of  physical  examinations,  the  laboratory  findings, 
etc.    Then  they  are  appreciated  and  of  value;  not  otherwise. 

So  with  her  educational  therapy.  It  will  often  go  wide  of  the 
mark,  unless  ;t  is  supervised  (like  X-ray  treatment  or  massage)  by  the 
doctor  in  charge  of  the  case. 

To  turn  a  patient  over  to  the  social-service  department  once  for  all 
is  a  common  but  wholly  mistaken  practice. 

Why  has  the  work  described  here  arisen  only  since  1905? 

Because  of  the  development  of  big  Out-Patient  Clinics  where  team 
work  of  many  takes  the  place  of  one's  doctor's  attempt  to  do  everything 
himself.  The  development  of  diagnostic  and  therapeutic  teams  and 
with  this  the  stratification  of  medical  jobs  so  that  untrained  people  can 
do  much  of  the  job,  leaving  the  doctor  for  his  expert  work,  has  helped 
to  show  us  how  many-sided  is  the  task  of  helping  a  sick  person  towards 
recovery. 

In  the  division  of  labor  thus  developed,  place  is  found  for  one  who 
deals  in  details,  who  knows  the  patient  in  his  home,  his  work  and  his 
school,  and  who  gradually  becomes  competent  to  trace  out  and  record 
the  mental  elements  present  in  all  organic  disease  as  well  as  in  func- 
tional or  neurotic  maladies. 

This  is  the  most  important  point  in  the  whole  matter.  Mental 
elements  in  the  causation,  in  the  symptomatology,  in  the  prognosis  and 
treatment  of  disease  are  recognized  today  more  fully  than  ever  before. 

We  know  today  more  than  we  ever  did  before  what  worry,  fear, 


744  MEDICAL-SOCIAL  SERVICE 

grief,  and  other  emotional  strains  can  do  in  modifying  and  augmenting 
and  prolonging  disease.  We  also  know  something  of  what  peace  of 
mind,  habits  of  concentration,  recreative  enjoyment,  satisfaction  in 
work,  friendship  or  religion  can  do  to  banish  or  to  alleviate  disease. 

No  medical-social  worker  is  an  expert  fit  to  succeed  often  in  under- 
standing or  manipulating  all  these  delicate  and  pervasive  forces.  But 
when  she  is  born  for  her  job  and  then  trained  on  it,  she  can  contribute 
perhaps  as  much  to  the  hospital  team  work  as  any  single  person  in  it. 

It  is  in  organized  medicine,  then,  as  we  have  it  in  the  best  modern 
hospitals,  sanitoria,  schools,  and  factories  that  medical-social  service 
has  its  chief  function.  Whenever  medical  organization  takes  a  step 
forward,  whenever  group  medicine  in  any  form  progresses,  the  sort  of 
aid  and  technique  here  described  will,  I  believe,  find  a  part. 


CHAPTER  XX-A 
PSYCHOSOMATIC   MEDICINE 

Bv   EDWARD   WEISS 

Table  of  Contents 

Introduction 744 

Psychosomatic  Problems  in  the  Practice  of  Medicine 744 

The  Present  Management  of  Psychosomatic  Problems 744 

The  Illness  Is  "  Functional " 744 

Suspicion  of  Physical  Disease 744 

Pathological  Curiosities 744 

The  Organic  Tradition  in  Medicine 744 

Diagnostic  Problems  in  Psychosomatic  Medicine 744 

The  Either-Or  Concept 744 

Functional  and  Organic 744 

The  Nature  of  Emotional  Problems 744 

Psychopathology 744 

Influence  of  Childhood  Environment 744 

The  Role  of  Anxiety 744 

The  Feeding  Process 744 

The  Components  of  Anxiety 744 

The  Unconscious 744 

Anxiety  and  the  Gastrointestinal  Tract 744 

Organ  Neurosis 744 

Relation  of  Symptoms  to  Life  Situation 744 

Psychosomatic  Study  in  Illness 744 

The  Anxiety  Attack 744 

Organ  Language 744 

Sexual  Factors 744 

Psychotherapy 744 

What  Is  Psychotherapy? 744 

Major  and  Minor  Psychotherapy 744 

Cost  of  Psychotherapy 744 

Summary 744 

Bibliography 744 


Introduction 


10) 
) 
) 
12) 
13) 
13) 
13) 
14) 
14) 
15) 
18) 
21) 
22) 

23) 
24) 
24) 

25) 
26) 
26) 
27) 


Psychosomatic  is  a  new  term,  but  it  describes  an  approach  to  medicine  as  old 
as  the  art  of  heahng  itself.    It  is  not  a  speciality  but  rather  a  point  of  view  which 
Vol.  I.  445 

744  (i) 


744  (2)  PSYCHOSOMATIC   MEDICINE 

applies  to  all  aspects  of  medicine  and  surgery.  It  does  not  mean  to  study  the 
soma  less;  it  only  means  to  study  the  psyche  more.  Its  subject  matter  is  founded 
on  the  important  advances  in  physical  medicine  as  well  as  on  the  biologically 
oriented  psychology  of  Freud  without  whose  epochal  discoveries  no  work  on 
psychosomatic  medicine  could  be  attempted.  Following  these  discoveries,  Felix 
Deutsch,  then  of  Vienna,  and  Jelliffe  in  America  applied  this  new  psychopathology 
to  general  medical  problems.  Later  Alexander  and  his  associates  at  the  Chicago 
Institute  of  Psychoanalysis,  Karl  and  William  Menninger  of  Topeka,  Halliday 
of  Scotland  and  Dunbar  and  her  associates  at  the  Presbyterian  Hospital  in  New 
York  by  their  important  researches  added  materially  to  our  knowledge  of  this 
subject.  In  1935  Dunbar  in  addition  to  her  valuable  studies  performed  the  great 
service  of  collecting  the  widely  scattered  literature  in  this  field  under  the  title 
"Emotions  and  Bodily  Changes^".  The  epochal  discoveries  of  Freud,  the  re- 
searches mentioned,  and  the  compilation  of  literature  by  Dunbar  as  well  as  the 
contributions  of  many  others  are  all  used  freely  in  the  following  discussion. 

Physicians  have  always  known  that  the  emotional  life  had  something  to  do 
with  illness,  but  the  structural  concepts  introduced  by  Virchow  led  to  the  separa- 
tion of  illness  from  the  psyche  of  man  and  to  a  consideration  of  disease  as  only  a 
disorder  of  organs  and  cells.  With  this  separation  of  diseases  into  many  different 
ailments  came  the  development  of  specialists  to  attend  to  all  of  these  distinct 
diseases.  With  the  specialists  came  the  introduction  of  instruments  of  precision, 
and  the  mechanization  of  medicine  began.  Medicine  now  contented  itself  with 
the  study  of  the  organism  as  a  physiological  mechanism,  impressed  by  blood 
chemistry,  electrocardiography  and  other  methods  of  physical  investigation,  but 
unimpressed  by,  and  indeed  often  holding  in  contempt,  the  psychological  back- 
ground of  the  patient,  which  was  considered  not  so  scientific  as  the  results  of 
laboratory  studies.  This  period  may,  in  truth,  be  referred  to  as  the  "machine 
age  in  medicine".  It  is  not  to  be  denied  that  remarkable  developments  have 
occurred  during  this  period  of  laboratory  ascendancy,  but  it  also  must  be  ad- 
mitted that  the  emotional  side  of  illness  has  been  almost  entirely  neglected. 

Psychosomatic  Problems  in  the  Practice  of  Medicine 

Defined  as  bodily  disorders  whose  nature  can  be  appreciated  only  when  emo- 
tional factors  are  investigated  in  addition  to  physical  factors,  psychosomatic  af- 
fections can  be  studied  in  the  following  manner. 

(i)  Between  the  small  number  of  obviously  psychotic  persons  whom  a  phy- 
sician sees  and  the  larger  number  of  patients  who  are  sick  solely  because  of 
physical  disease  in  which  emotional  factors  play  no  part  are  a  vast  number  of 
sick  people  who  are  not  "out  of  their  minds"  and  yet  who  do  not  have  any 
definite  bodily  disease  to  account  for  their  illness.     Psychosomatic  medicine  is 

Vol.  I.  445 


PSYCHOSOMATIC   PROBLEMS   IN   MEDICINE      744  (3) 

much  concerned  with  such  patients.  It  is  estimated  reliably  that  about  a  third 
of  the  patients  who  consult  a  physician  fall  into  this  group.  These  are  the  so- 
called  purely  "functional"  problems  of  medical  practice. 

(2)  Another  large  group  of  patients,  who  consult  a  physician,  have  symptoms 
that  are  in  part  dependent  upon  emotional  factors,  even  though  organic  changes 
of  non-psychogenic  origin  are  present.  This  second  group  is  even  more  im- 
portant than  the  first  from  the  standpoint  of  diagnosis  and  treatment.  These 
psychosomatic  problems  often  are  very  complicated,  and  because  serious  organic 
disease  may  be  present,  the  psychic  factor  is  capable  of  doing  more  damage  than 
in  the  first  group.  This  phase  of  the  subject  is  especially  well  illustrated  by  many 
instances  of  organic  heart  disease.  For  while  a  neurotic  with  a  normal  heart  may 
suffer  a  great  deal  subjectively  and  may  even  have  a  disturbance  of  cardiac  func- 
tion marked  by  various  forms  of  arrhythmia,  the  heart,  certainly  in  the  majority 
of  such  patients,  remains  structurally  healthy.  But  the  neurotic  patient,  who  has 
organic  heart  disease,  may  add  a  real  burden  to  the  work  of  his  heart  either  through 
constant  tension  of  psychic  origin  or  more  especially  by  means  of  acute  episodes 
of  emotional  origin.  This  may  hasten  a  cardiac  breakdown  which  might  be 
postponed  indefinitely,  if  there  were  no  psychic  stress.  Thus  the  psychic  factors 
may  be  even  more  important  than  the  physical  in  producing  incapacity. 

(3)  Psychosomatic  medicine  is  much  interested  in  disorders  generally  con- 
sidered wholly  within  the  realm  of  "physical  disease",  which  have  to  do  with 
the  vegetative  nervous  system,  such  as  migraine,  asthma,  peptic  ulcer  and  essen- 
tial hypertension.  It  is  believed  that  psychic  factors  may  be  of  great  importance 
in  their  etiology  and  even  more  importantly  in  their  management. 

(4)  Here  we  touch  upon  a  fourth  problem,  related  to  2  and  3,  in  which  studies 
are  just  beginning  to  be  made,  that  is,  the  possible  relationship  of  psychological 
disturbances  to  structural  alteration.  The  viewpoint  of  disease  bequeathed  to 
us  from  the  nineteenth  century  could  be  indicated  in  the  following  formula: 

Cellular  disease  — >  Structural  alteration  — >  Physiological  (or  functional) 
disturbance. 

In  the  twentieth  century  this  formula  underwent  alteration  in  some  situa- 
tions. For  example,  in  essential  hypertension  and  vascular  disease  the  formula 
was  altered  to  read : 

Functional  disturbance  — >  Cellular  disease  -^  Structural  alteration. 

We  are  still  in  the  dark  as  to  what  may  precede  the  functional  disturbance 
as  in  the  example  just  cited  of  essential  hypertension  and  the  resulting  vascular 
disease.  It  seems  possible  that  future  investigations  will  permit  us  to  say  that 
it  is  possible  for  a  psychological  disturbance  to  antedate  the  functional  altera- 
tion.   Then  the  formula  would  read: 

Vol.  I.  445 


774  (4)  PSYCHOSOMATIC   MEDICINE 

Psychological  disturbances  — >  Functional  impairment  — >  Cellular  disease  — > 
Structural  alteration. 

With  the  last  problem,  however,  this  discussion  is  not  greatly  concerned.  It 
is  restricted  for  the  most  part  to  known  psychosomatic  relationships,  in  other 
words,  a  discussion  of  clinical  problems  for  which  there  are  immediate  practical 
applications. 


The  Present  Management  of  Psychosomatic  Problems 
The  Illness  Is  "Functional^' 

How  does  modern  medicine  handle  these  patients?  When  we  review  our 
present  management,  we  find  that  the  patients  in  group  (i)  are  commonly  told 
that  no  organic  disease  is  present  and  that  the  whole  thing  is  "functional". 
They  are  dismissed  often  without  further  care,  only  to  land  eventually  in  the 
hands  of  some  irregular  practitioner  or  quack  healer.  Certainly  in  dealing  with 
many  of  these  patients  it  is  necessary  to  do  more  than  assure  the  patient  of  the 
absence  of  physical  disease.  Nor  does  it  do  to  dismiss  a  patient  with  the  state- 
ment that  his  illness  is  "functional".  To  the  physician  this  term  usually  means 
"psychogenic",  although  he  does  not  always  admit  it,  even  to  himself.  All  kinds 
of  twists  and  turns  are  taken  to  avoid  the  use  of  the  hated  term,  psychogenic. 
Often  "neurogenic"  replaces  it,  and  thus  the  physician  is  permitted  to  hold  on 
to  the  notion  that  somehow  there  is  a  physical  answer  to  the  problem.  This 
point  will  be  discussed  shortly. 

Hamman^  has  written  with  a  great  deal  of  understanding  on  this  subject: 
"When  I  was  a  student,  the  course  in  psychiatry  consisted  of  lectures  upon  in- 
sanity and  the  demonstration  of  patients  with  gross  disorders  of  thought  and 
conduct.  I  had  no  interest  in  the  topics  and  the  patients  distressed  and  dis- 
turbed me.  I  was  greatly  relieved  when  the  course  was  over  and  never  dreamed 
that  I  should  find  any  occasion  upon  which  to  apply  what  I  had  heard  and  seen. 
I  fully  determined  to  have  nothing  further  to  do  with  psychiatry  and  unfortu- 
nately I  held  very  obstinately  to  this  determination.  As  a  matter  of  fact,  I  still 
hold  to  it  as  regards  what  I  then  considered  to  be  the  province  of  psychiatry. 
I  say  that  this  determination  was  unfortunate  because  it  prevented  me  from 
understanding  what  is  the  true  domain  of  psychiatry,  and  so  blinded  me  that  it 
was  many  years  before  I  could  see  the  fruitful  application  of  psychiatry  to  the 
daily  problems  of  practice.  In  a  word,  the  practicing  physician  is  not  at  all  in- 
terested in  what  he  scornfully  regards  as  the  medicine  of  the  madhouse  and  the 
asylum;  but  he  is  vitally  interested  in  what  we  may  call  every  day  psychiatry. 
At  least  he  becomes  interested  in  it  when  his  interest  is  properly  aroused  by  the 
demonstration  of  the  importance  and  value  of  the  application  of  psychiatry  to 

Vol.  I.  445 


MANAGEMENT  OF   PSYCHOSOMATIC   PROBLEMS     744  (5) 

his  daily  work.  He  must  know  a  little  about  gross  disorders  of  the  mind,  but 
only  enough  to  see  clearly  that  these  extreme  alterations  are  merely  exaggerations 
of  trends  and  reactions  that  he  may  observe  in  himself,  in  his  friends,  in  his 
patients.  If  a  physician  is  once  persuaded  to  look  within  himself  and  to  learn 
to  identify  unaccountable  variations  in  mood  and  energy  as  the  analogue  of  a 
manic-depressive  cycle,  the  habit  of  ascribing  failure  and  disappointment  to  ill 
luck  or  persecution  as  the  promptings  of  paranoia,  day  dreams  (in  which  satis- 
faction is  secured  for  the  rubs  and  indignities  of  life  and  retributive  disaster 
showered  upon  enemies)  as  the  harmless  whisperings  of  schizophrenia,  certain  ex- 
aggerated reactions  as  the  masks  for  defeats  and  inadequacies,  various  somatic 
symptoms  as  excuses  for  retreat  from  difficult  or  unpleasant  situations,  he  will 
forever  have  an  enduring  interest  in  psychiatry." 

Suspicion  oj  Physical  Disease 

Sometimes  the  patient  is  told  that  the  physician  does  not  think  that  anything 
is  the  matter,  but  suspicion  is  cast  upon  some  organ  or  system  which  needs 
watching  and  care.  For  example,  the  patient  with  symptoms  referred  to  the 
heart  region  is  told  that  his  heart  is  all  right.  Nevertheless  he  is  cautioned  to 
rest,  medicine  is  given,  and  each  time  that  he  visits  the  physician  his  heart  is 
examined  again,  or  his  blood  pressure  is  taken.  It  is  impossible  to  eradicate  the 
suspicion  of  organic  disease  under  such  circumstances.  This  point  will  be  con- 
sidered later,  but  here  it  may  be  emphasized  that  in  dealing  with  the  majority 
of  "functional"  problems  we  must  examine  thoroughly,  satisfy  ourselves  as  to 
the  absence  of  physical  changes  and  then  stop  examining  with  the  firm  state- 
ment, "You  have  no  evidence  of  organic  disease". 

Pathological  Curiosities 

Very  frequently  following  "thorough  study"  by  means  of  the  usual  medical 
history  physical  examination  and  laboratory  investigation,  some  "pathologic 
curiosity"*  is  discovered,  which  really  has  nothing  to  do  with  the  illness,  but 
the  patient  then  is  treated  from  the  standpoint  of  disease  and  is  subjected  to 
unnecessary  medical  or  surgical  treatment,  which  in  many  instances  intensifies 
the  neurotic  condition.  For  example,  a  common  cause  of  fatigue  is  not  infection 
but  emotional  conflict  which  uses  up  so  much  energy  that  little  is  left  for  other 
purposes.  A  patient  with  chronic  fatigue  may  be  studied  from  every  possible 
physical  standpoint  and  finally,  especially  in  the  presence  of  long  continued, 
low  fever,  suspicion  rests  upon  minimal  and  obsolete  tuberculosis  of  the  lungs. 

*  By  "pathologic  curiosity"  is  meant  some  congenital  or  acquired  lesion  that  has  no 
significance  from  the  standpoint  of  the  present  ilkiess. 

Vol.  I.  445 


744  (6)  PSYCHOSOMATIC   MEDICINE 

Long  periods  of  rest  in  bed  or  sanitarium  may  follow.  The  error  in  the  study 
of  such  cases  is  the  fixation  on  physical  factors  and  the  absence  of  attention  to 
emotional  factors  so  that  the  physician  himself  becomes  a  "pathogenic  agent" 
in  helping  to  "fix  the  neurosis". 

In  other  words  the  attitude  of  modern  medicine  is  not  so  very  different  toward 
these  patients  from  that  described  in  1884  by  Clifford  Allbutt,-  the  great  English 
clinician,  who  said  in  speaking  of  the  visceral  neuroses :  "A  neuralgic  woman  seems 
thus  to  be  peculiarly  unfortunate.  However  bitter  and  repeated  may  be  her 
visceral  neuralgias,  she  is  told  either  that  she  is  hysterical  or  that  it  is  all  uterus. 
In  the  first  place  she  is  comparatively  fortunate,  for  she  is  only  slighted;  in  the 
second  case  she  is  entangled  in  the  net  of  the  gynecologist,  who  finds  her  uterus, 
hke  her  nose,  is  a  little  on  one  side,  or  again,  like  that  organ,  is  running  a  little, 
or  it  is  as  flabby  as  her  biceps,  so  that  the  unhappy  viscus  is  impaled  upon  a  stem, 
or  perched  upon  a  prop,  or  is  painted  with  carbolic  acid  every  week  in  the  year 
except  during  the  long  vacation  when  the  gynecologist  is  grouse-shooting,  or 
salmon-catching,  or  leading  the  fashion  in  the  Upper  Engadine.  Her  mind  thus 
fastened  to  a  more  or  less  nasty  mystery  becomes  newly  apprehensive  and  physi- 
cally introspective  and  the  morbid  chains  are  riveted  more  strongly  than  ever. 
Arraign  the  uterus,  and  you  fix  in  the  woman  the  arrow  of  hypochrondia,  it 
may  be  for  life." 

The  Organic  Tradition  in  Medicine 

As  a  consequence  of  this  structural  and  physiological  tradition  in  medicine  a 
large  number  of  physicians  pride  themselves  upon  their  unwillingness  to  concede 
the  absence  of  physical  disease  when  dealing  with  an  obscure  illness.  In  dis- 
cussing such  a  patient  they  are  apt  to  say  "but  there  must  be  something  the  mat- 
ter", meaning  that  there  must  be  a  physical  basis  for  the  illness.  And  they  further- 
more believe  that  future  researches  along  the  lines  of  physical  medicine  will 
eventually  uncover  the  hidden  causes,  infectious,  allergic,  endocrine  or  meta- 
bolic, responsible  for  such  obscure  illnesses. 

Still  another  group  of  physicians  are  willing  to  believe  that  psychic  factors 
have  something  to  do  with  illness,  but  they  have  only  a  vague  notion  of  the 
part  that  such  factors  play.  These  physicians  recognize  that  there  is  a  "neuro- 
genic factor"  or  a  "large  nervous  element"  present,  but  they  look  upon  this 
feature  as  a  secondary  one  and  probably  a  consequence  of  the  physical  disorder. 
While  freely  acknowledging  the  relation  of  psychic  causes  to  such  physiological 
phenomena  as  blushing,  weeping,  gooseflesh,  vomiting  and  diarrhea,  nevertheless 
they  find  it  difficult  to  believe  that  more  prolonged,  chronic  disturbances  of  a 
physiological  nature  possibly  can  be  psychic  in  origin. 

They  are  the  physicians,  who  often  remark  about  a  patient,  "but  he  does 
not  look  neurotic",  perhaps  imagining  that  such  a  patient  should  by  his  general 

Vol.  I.  445 


DIAGNOSIS   IN  PSYCHOSOMATIC   MEDICINE       744(7) 

apprehension  or  by  evidences  of  physical  nervousness  betray  the  fact  that  neu- 
rosis is  present.  Their  approach  to  the  emotional  problem  is  apt  to  consist  of 
the  question,  "Are  you  worried  about  anything?"  Unfortunately  most  neu- 
rotics do  not  betray  their  neurosis  in  their  appearance,  nor  is  the  approach  to 
their  emotional  problem  so  simple  that  the  direct  question,  "Are  you  worried 
about  anything?",  will  produce  material  of  importance. 

Diagnostic  Problems  in  Psychosomatic  Medicine 

More  specifically  then,  what  are  some  of  the  diagnostic  and  therapeutic 
problems  of  psychosomatic  medicine  and  how  are  they  to  be  approached? 

First,  there  is  the  failure  to  recognize  neurosis  and  treatment  of  the  patient 
as  "organically"  diseased.  This  happens  most  frequently,  as  already  suggested, 
because  modern  clinical  medicine  attempts  to  establish  the  diagnosis  of  "func- 
tional" disease  by  ruling  out  "organic"  disease  through  medical  history,  physical 
examination  and  laboratory  investigation.  The  point  that  I  particularly  wish 
to  make  is  that  the  diagnosis  of  "functional"  illness  must  be  established  not 
simply  by  exclusion  of  "organic"  disease  but  on  its  own  characteristics  as  well. 
In  other  words  neurosis  has  its  own  distinctive  features  to  be  discovered  by  psy- 
chosomatic study,  for  only  in  this  way  can  serious  errors  in  diagnosis  and  treat- 
ment be  avoided.  If  the  above  statements  are  admitted  to  be  correct,  it  must 
follow  that  personality  study  is  just  as  unportant  in  the  problems  of  illness  as 
laboratory  investigation. 

This  kind  of  approach  will  do  a  great  deal  to  relieve  the  fear  of  the  physician 
that  he  is  missing  something  organic,  because  it  will  supply  him  with  additional 
information  to  confirm  his  diagnosis  of  functional  disease.  It  is  perfectly  true, 
of  course,  that  structural  alterations  can  be  overlooked  and  the  patient  treated 
only  as  a  functional  case,  which  is  the  reverse  of  the  situation  above  mentioned. 
Physicians  are  constantly  harassed  by  this  fear  of  overlooking  "organic"  disease. 
They  are  of  the  opinion,  when  dealing  with  this  class  of  patients,  that  the  struc- 
tural disease  is  hidden  and  will  come  to  light  with  the  passage  of  time.  Again 
this  may  be  true  but  in  the  majority  of  instances  is  not. 

A  recent  study  from  the  Mayo  Clinic  is  illuminating  in  this  regard.  Macy 
and  Allen^  studied  the  records  of  235  patients  approximately  six  years  after  the 
diagnosis  of  chronic  nervous  exhaustion,  had  been  made  with  the  idea  that,  if 
the  clinical  picture  at  the  first  examination  was  due  to  unrecognized  "organic" 
disease,  such  "organic"  disease  should  be  detected  by  subsequent  examinations 
over  a  period  of  years.  The  accuracy  of  the  diagnosis  proved  to  be  94  per  cent., 
which  seems  to  indicate  that  this  kind  of  "functional"  illness,  at  any  rate,  is 
not  due  to  "organic"  disease.  It  is  interesting  to  note  in  passing  that  289  sepa- 
rate operations  had  been  performed  on  200  patients  of  the  group  that  they  studied. 

Vol.  I.  445 


744  (8)  PSYCHOSOMATIC   MEDICINE 

The  "Either-Or''  Concept 

When  emotional  factors  are  associated  with  actual  "organic"  changes,  too 
little  attention  is  paid  to  the  emotional  factors.  The  feeling  exists  and  the  state- 
ment is  made  that  "the  physical  findings  are  sufficient  to  account  for  the  illness". 
In  this  connection  let  me  again  emphasize  that  just  as  we  cannot  limit  ourselves 
simply  to  the  exclusion  of  "organic"  disease  in  dealing  with  the  purely  "func- 
tional "  group,  so  even  more  importantly  in  the  second  group  is  there  the  necessity 
for  not  resting  content  with  the  finding  of  an  "organic"  lesion.  The  day  is  near 
at  hand  for  the  final  outmoding  of  the  "either-or"  concept,  either  functional  or 
organic,  in  diagnosis  and  to  place  in  its  stead  the  idea  of  how  much  of  one  and 
how  much  of  the  other,  that  is,  how  much  of  the  problem  is  emotional  and  how 
much  is  physical  and  what  is  the  relationship  between  them.  This  is  truly  the 
psychosomatic  concept  of  medicine. 

In  a  well  written  and  remarkably  lucid  consideration  of  the  "cause"  of  illness 
Halliday^  indicated  the  approach  to  this  complicated  problem  with  a  simple 
illustration. 

Let  us  take,  says  Halliday,  a  fragment  of  conversation,  which  may  be  over- 
heard when  a  toddler  begins  to  howl  in  the  street. 

Onlooker  to  mother:  "Why  is  he  crying?" 
Mother:  "Oh,  he  cries  at  anything;  he  is  just  a  baby". 
Small  brother:  "He  saw  a  cat  and  it  frightened  him". 
Onlooker:  "Well,  he  has  got  a  fine  pair  of  lungs  anyway". 

"These  remarks  provide  an  explanation  of  the  child's  mode  of  behavior  in' 
terms  of  the  three  fields  of  etiological  discourse.  In  the  field  of  the  individual 
the  cause  is  announced  to  be  the  characteristic  of  'being  a  baby':  in  the  field 
of  environment  the  encounter  with  a  cat:  in  the  field  of  mechanism  the  lungs  in 
their  instrumental  perfection.  It  will  be  noted  that,  if  any  mode  of  behavior 
is  to  take  place,  'cause'  must  operate  in  all  three  fields  at  a  particular  point 
in  time.  In  the  example  quoted,  we  may  assume  that  the  behaviour  called  cry- 
ing would  not  have  appeared  in  the  absence  of  (a)  the  characteristic  of  being  a 
baby,  or  (b)  the  environment  factor  of  the  cat,  or  (c)  the  mechanism  integrity  of 
the  respiratory  organs." 

Halliday  then  explains  that,  when  the  findings  as  to  cause  in  each  of  the 
three  fields  of  "etiological  discourse"  can  be  related  to  one  another,  we  may 
say  that  the  illness  is  explained.  Thus,  in  diphtheria  "the  cause  in  the  first  field 
is  the  characteristic  summarized  by  the  phrase  'being  Schick-positive';  cause 
in  the  second  field  is  an  encounter  with  the  diphtheria  bacillus;  cause  in  the 
third  field  is  the  toxin  produced  on  the  fauces  .  .  ." 

When  we  think  in  terms  of  the  psychosomatic  point  of  view,  we  must  employ 

Vol.  I.  445 


DIAGNOSIS   IN  PSYCHOSOMATIC   MEDICINE      744  (9) 

the  same  approach.  Thus  in  peptic  ulcer  we  must  think  (i)  of  the  individual, 
"what  kind  of  person  is  he?"  (predisposition,  physical  and  psychological);  (2)  of 
the  environment,  "what  has  he  met?"  (tobacco  and  food,  social  and  psychological 
problems),  and  (3)  of  mechanism,  "what  happened?"  (vascular  supply,  hyper- 
acidity, hypermotility,  etc.) 

Here  the  psychic  element  is  an  integral  part  of  the  study,  one  of  many  and 
diverse  etiological  factors,  emerging  at  various  levels  of  the  personality  develop- 
ment. 

At  this  point  it  may  not  be  amiss  to  quote  further  from  Halliday  in  regard 
to  that  long  confused  subject  "functional"  versus  "organic"  disease. 

Functional  and  Organic 

"Another  source  of  obscurity  is  to  confuse  the  technique  of  approach  with 
the  object  of  study.  A  common  example  is  the  mysterious  phrase  'mind  and 
body'.  This  seems  to  indicate  that  an  individual  is  composed  of  two  distinct 
and  contrasted  entities,  a  mind  entity  and  a  body  entity.  If  the  phrase  has 
any  meaning,  it  is  this;  the  individual  may  be  studied  by  a  psychological  ap- 
proach, and  the  individual  may  be  studied  by  a  structural  or  physical  approach. 
It  is  our  techniques  or  methods  of  investigation  which  are  diverse  and  multiple, 
not  the  individual,  who  is  a  unity." 

"The  words  functional  and  organic  suggest  that  illness  may  be  divided  into 
two  distinct  kinds,  and  much  has  been  written  on  this  faulty  premise.  For  ex- 
ample, it  has  been  stated  that,  if  an  unorthodox  healer  cures  a  patient,  the  illness 
must  have  been  functional  and  presumably  not  the  concern  of  the  scientific 
medical  man,  who  deals  only  in  true  or  organic  illness.  Again,  it  has  been  stated 
that  the  word  "functional"  is  applicable  to  a  morbid  process  which  is  "reversible". 
But  what  of  lobar  pneumonia,  warts  and  on  occasion  even  lipoma?  A  little  con- 
sideration shows  that  the  words  organic  and  functional  are  merely  examples  of 
technical  slang,  which  express  in  convenient  form  the  following:  In  certain  ill- 
nesses or  in  certain  stages  of  these  illnesses  a  structural  technique  or  approach, 
e.g.  anatomical,  histological,  provides  a  positive  finding;  in  slang  terms  the  ill- 
ness is  organic.  In  other  illnesses  the  application  of  the  structural  approach  pro- 
vides a  negative  finding,  whereas  the  application  of  other  techniques  of  approach 
provides  a  positive  finding;  in  slang  terms  the  illness  is  functional.  Many  writers, 
failing  to  appreciate  the  only  meaning  which  can  be  given  to  these  terms,  seem 
to  have  imagined  that  by  using  them  a  fundamental  etiological  basis  for  the 
division  of  illness  has  been  achieved." 

The  following  diagrams  are  used  frequently  in  illustrating  this  topic.  Fig.  i 
illustrates  the  usual  approach  in  the  study  of  illness  which  presumably  will  lead 
to  a  diagnosis.    It  consists  of  the  bare  facts  of  the  medical  history,  the  physical 

Vol.  1.  445 


744  (lo) 


PSYCHOSOMATIC   MEDICINE 


examination  and  the  various  laboratory  investigations.  It  is  diagnosis  by  ex- 
clusion and  fails  in  so  many  instances  simply  because  the  life  situation  of  the 
patient,  in  other  words,  a  study  of  the  emotional  life,  which  may  provide  the  key 
to  the  solution  of  the  problem,  is  neglected  completely  or  at  most  investigated 
inadequately.  The  proper  psychosomatic  approach  is  shown  in  Fig.  2  where 
the  personality  study  occurs  at  the  same  time  as  the  physical  and  laboratory  study. 


Laboratory 
Studies 


Laboratory 
Studies 


Fig.  I* 


J'hv., 


Diagnosis  by 
Exclusion 


Psychosomatic 
Diagnosis  and 
Treatment 


Fig.  2 


The  Nature  of  Emotional  Problems 

We  know  that  these  patients  have  been  badly  handled.  Can  we  do  any 
better?  What  is  the  matter  with  them  and  how  should  they  be  treated?  First 
of  all  let  us  say  that  these  patients  are  suffering  from  disturbances  in  their  emo- 
tional lives;  that  is,  the  illness  is  whoUy  or  in  part  of  psychological  origin  and  can 
be  studied  satisfactorily  and  treated  only  if  this  factor  is  dealt  with  adequately. 
The  ill  health  arises  in  a  predisposed  individual  usually  from  long  standing  dis- 
satisfactions in  the  business,  social  or  home  life,  and  this  failure  of  adjustment 
to  environment  is  manifested  by  a  disturbance  in  some  part  of  the  personality 
either  as  bodily  symptoms  of  various  kinds  capable  of  mimicking  almost  any 
disease  or  as  affections  of  the  spirit  resulting  in  attacks  of  anxiety,  obsessions, 
phobias,  depression  and  other  disturbances  of  mood.  What  is  not  so  generally 
realized  is  that  the  mere  discovery  of  the  so-called  dissatisfactions  or  unpleasant 
occurrences  in  the  life  situation  of  the  individual  is  not  a  sufficient  explanation 
nor  even  an  adequate  indication  of  the  psychic  background  of  the  illness.  In 
*  From  Weiss,  E.,  and  English,  O.  S.:   Psychosomatic  Medicine,  p.  7.^" 

Vol.  I.  445 


PSYCHOPATHOLOGY  744(11) 

other  words,  besides  excluding  physical  disease  in  the  one  case  and  correctly 
evaluating  the  part  it  plays  in  another,  it  is  of  the  greatest  importance  to  know 
the  patient's  ability  to  adjust  to  certain  life  situations,  his  pattern  of  reacting 
to  them,  the  degree  of  anxiety  in  his  make-up  and  the  nature  and  seriousness  of 
his  conflicts.  Psychosomatic  study  is  necessary,  if  we  are  to  establish  a  specific 
relationship  of  the  psychic  situation  to  the  personality  of  the  individual.  Just 
as  the  typhoid  bacillus,  specific  for  typhoid  fever,  depends  upon  the  susceptibility 
of  the  individual,  so  does  specificity  of  the  psychic  event  depend  upon  person- 
ality structure  of  the  person.  To  make  such  studies  one  must  have  some  train- 
ing in  psychopathology.  When  psychopathology  is  given  an  equal  place  with 
tissue  pathology  in  our  medical  curriculum  and  is  as  well  taught,  we  will  finally 
realize  that  psychotherapy  is  an  integral  part  of  our  medical  discipline. 

Psychopathology 

It  would  seem  that  we  are  rapidly  approaching  such  an  understanding.  The 
great  impetus  given  to  this  subject  by  military  medicine  surely  will  result  in 
the  proper  emphasis  in  medical  teaching.  It  can  be  truly  said  that  World  War  I 
established  psychiatry  on  a  firm  scientific  basis,  and  World  War  II  is  seeing  its 
final  integration  into  general  medicine,  in  other  words,  psychosomatic  medicine. 
When  this  integration  has  been  satisfactorily  accomplished,  there  will  no  longer 
be  need  for  the  term,  psychosomatic;  both  parts  of  the  term  will  be  implicit 
in  the  word  medicine. 

It  is  impossible  in  a  short  discussion  to  cover  the  subject  of  psychopathology. 
Only  a  few  principles  can  be  mentioned.  There  is  no  sharp  line  between  normal 
and  neurotic.  Anyone  may  "break  under  pressure",  in  other  words,  become 
neurotic.  Witness  the  combat  neuroses  of  World  War  II;  robust  men  with  pre- 
viously healthy  personalities  succumbed  to  "combat  fatigue",  when  enough  pres- 
sure was  put  upon  them.  The  same  thing  is  true  in  civil  life,  although  not  so 
common.  Generally  speaking  persons,  who  develop  severe  psychosomatic  dis- 
orders or  pronounced  neurotic  disturbances,  are  people  who  have  been  predis- 
posed by  psychopathology  established  early  in  life.  In  other  words  an  adult 
neurosis  depends  to  a  great  extent  upon  a  childhood  neurosis. 

Influence  of  Childhood  Environment.  —  A  point  of  view  which  I  have  tried 
to  stress  is  that  for  the  most  part  psychotherapy  is  necessary  because  our  edu- 
cational processes  are  confined  to  the  intellect.  In  other  words  our  children 
receive  scientific  management  from  an  intellectual  standpoint,  but  for  a  variety 
of  reasons,  mainly  constitutional  and  family  influences,  the  emotional  growth 
is  stunted.  It  is  the  retarded  emotional  development  which  is  fundamentally 
responsible  for  psychosomatic  illness.  In  other  words,  if  the  intellectual  age  and 
the  emotional  age  differ  sharply,  the  background  for  illness  of  psychological  origin 

Vol.  I.  445 


744  (i2)  PSYCHOSOMATIC   MEDICINE 

exists.  One  might  go  further  to  say  that  man  has  four  ages,  first,  his  chronological 
age,  second,  his  physical  age,  third,  his  intellectual  age  and  fourth,  his  emotional 
age.  For  example,  one  easily  can  think  of  an  adult,  who  is  chronologically  forty, 
physically  fifty,  intellectually  twelve  and  emotionally  only  five.  And  it  might 
be  said  that,  if  these  various  ages  are  in  harmony,  he  is  apt  to  be  well,  and  if 
they  are  in  disharmony,  he  is  apt  to  be  ill.  Such  persons,  and  the  world  is  full 
of  them,  furnish  the  soil  for  the  development  of  psychosomatic  illness.  Psycho- 
therapy is  a  process  which  aims  to  bring  about  reeducation  of  the  emotions  and 
the  psychosomatic  approach  takes  cognizance  of  all  factors,  physical,  intellectual 
and  emotional. 

It  is  not  unusual  for  physicians  to  recommend  pregnancy  and  parenthood  as 
a  cure  for  neurotic  illness,  instability  in  the  husband  or  threatened  divorce  or 
separation.  This  prescription  is  rarely,  if  ever,  of  value.  It  is  a  pretty  safe  rule 
that  the  unstable  person  will  not  be  helped  by  becoming  a  parent  but  usually 
will  be  made  worse  as  a  result  of  the  added  responsibility.  How  often  upon  taking 
the  history  of  neurotic  persons,  and  especially  women,  do  wejiear,  "I  was  per- 
fectly well  until  my  first  child  was  born;  I  haven't  had  a  well  day  since."  It  is 
true  that  some  neurotic  women  will  feel  better  during  pregnancy,  but  they  pay 
dearly  for  their  short  period  of  improvement.  Nor  should  the  cost  to  the  child 
be  forgotten.  Not  only  does  parenthood  not  cure  neurosis,  but  it  prepares  the 
way  for  another  spoiled  life,  because  this  is  surely  one  of  the  ways  in  which 
neurosis  is  perpetuated.  The  atmosphere  of  the  home,  in  which  there  is  serious 
emotional  maladjustment,  creates  the  culture  medium  for  the  development  of 
further  emotional  problems.  This  is  the  real  "social  disease".  The  advice  to  an 
incompatible  couple,  "What  you  need  is  a  child  —  then  you  will  have  a  common 
interest",  is  as  unenlightened  as  it  is  dangerous.  While  it  may  succeed  in  holding 
the  marriage  together,  who  can  say  how  many  children  thus  are  sacrificed  on 
the  altar  of  incompatibility. 

Pregnancy,  like  marriage,  is  an  excellent  institution  and  undoubtedly  will 
persist,  but  it  is  not  to  be  recommended  for  therapeutic  reasons.  My  feeling  is 
that  we  must  reverse  the  process  of  recommending  parenthood  for  emotional 
maladjustment  and  instead  advise  birth  control  until  there  is  adequate  emo- 
tional development  for  rearing  a  child. 

What  has  just  been  said  suggests  that  there  is  such  a  thing  as  "psychological 
infection"  and  that  the  atmosphere  of  the  home  is  the  source  of  contagion. 

The  Role  of  Anxiety.  —  The  central  problem  of  disturbances  of  emotional 
origin  is  anxiety.  One  cannot  be  well  oriented  in  the  field  of  psychiatry  or  psycho- 
somatic medicine  without  considerable  knowledge  of  the  role  of  anxiety  in  the 
development  of  illness  of  emotional  origin.  It  lies  at  the  root  of  all  psycho- 
pathology  and  for  that  matter  plays  an  important  part  in  normal  behavior.  The 
human  being  from  birth  onward  has  a  need  for  optimum  conditions  of  comfort 

Vol.  I.  445 


PSYCHOPATHOLOGY  744  (13) 

as  the  growth  processes  advance.  During  the  first  months  of  hfe  the  body  needs 
food  and  warmth  not  only  because  of  their  importance  for  physical  growth  but 
also  for  emotional  satisfaction.  The  world  of  the  infant  is  small,  and  what 
would  seem  to  be  of  little  consequence  in  the  life  of  the  adult  may  be  of  primary 
importance  in  his  life. 

The  Feeding  Process.  —  The  sensual  pleasure  derived  from  the  feeding  process 
is  an  example.  The  total  nutritional  process  will  leave  a  pleasant  memory  im- 
pression upon  the  mind,  if  the  good  will  and  esteem  of  those  who  take  eare  of 
the  child  are  added  to  the  feeding  process.  A  sufficiency  of  food  of  the  right  kind, 
given  at  regular  intervals  and  administered  by  one  who  loves  the  child,  does 
much  to  lay  the  groundwork  for  a  relaxed  personality  which  feels  the  world  to 
be  a  friendly  place.  Thus  the  nutritional  process,  a  feeling  of  security  and  the 
capacity  to  love  are  blended  harmoniously. 

If,  on  the  other  hand,  there  is  insufficient  food  or  a  sudden  change  in  the 
type  of  food  or  method  of  feeding,  or  if  there  is  impatience  or  hostility  on  the 
part  of  the  one  who  feeds  the  child,  then  the  distress  of  hunger  or  of  cold  or  the 
lack  of  emotional  warmth  produce  anxiety.  There  seems  to  be  a  blind  sense, 
which  we  may  be  permitted  to  call  instinct,  that,  if  such  conditions  continue  long 
enough,  death  will  ensue.  In  the  beginning  this  apprehension  that  something 
threatens  the  integrity  of  the  self  is  a  reflex  pattern,  and  as  a  matter  of  fact  much 
of  it  remains  reflex  throughout  life.  An  important  part  of  the  therapeutic  edu- 
cational process  is  the  effort  to  help  the  individual  to  understand  the  source  of 
his  anxiety  and  to  teach  him  what  he  must  do  to  relieve  it.  It  is  fundamental 
to  our  understanding  of  personality  development  to  realize  how  much  basic  in- 
security and  resulting  anxiety  may  occur  through  deprivation  of  food,  warmth 
or  love  or  through  misunderstanding  of  the  physiological  rhythms  during  the 
early  weeks  and  months  of  life,  and  that  such  difficult  situations  in  the  life  of  a 
child  will  produce  anxiety  through  a  definite  physiological  mechanism. 

The  Components  of  Anxiety.  —  Anxiety  has  two  elements,  a  psychic  and  a 
somatic  or  physiological  component.  The  psychic  component  of  anxiety  is  the 
sensory  cortical  registration  of  displeasure  and  apprehension,  the  instinctual 
awareness  that  something  is  wrong,  and  the  somatic  component  is  the  motor 
response  of  rapid  heart  action,  rapid  or  embarrassed  respiration,  flushing,  per- 
spiration and  even  a  disturbance  in  the  function  of  the  gastrointestinal  tract. 
Anxiety  can  make  its  effects  felt  in  every  tissue  of  the  body,  although  in  many 
cases  it  seems  to  limit  its  expression  predominantly  to  those  organs  and  tissues 
supplied  by  the  autonomic  nervous  system. 

The  Unconscious.  —  Parents,  unaware  of  the  serious  efifects  of  trauma  and 
deprivation  in  the  life  of  the  child,  may  permit  much  psychopathology  in  the  form 
of  anxiety  to  develop  in  the  first  year  of  life.  Unwanted  children  are  neglected 
often  and  fed  carelessly  as  to  rhythm  or  improperly  as  to  the  type  of  food,  or 

Vol.  I.  445 


744  (i4)  PSYCHOSOMATIC   MEDICINE 

they  are  weaned  forcibly  and  without  regard  for  the  limited  adaptive  powers 
of  the  infant  to  a  new  experience.  Depending  upon  the  constitution  of  the  in- 
fant, such  treatment  is  apt  to  cause  anxiety.  Memory  impressions  are  made, 
and  psychological  reflexes  are  built  up.  These  patterns  are  "forgotten"  with 
the  passing  of  time,  but  if  numerous  or  highly  charged  with  anxiety,  they  may 
form  the  nucleus  of  illness  later  on.  Very  little  of  what  happens  to  us  is  truly 
forgotten.  Each  event  is  registered  on  the  brain  as  a  memory  with  varying  de- 
grees of  clearness,  and  what  cannot  be  recalled  is  referred  to  as  unconscious. 
That  part  of  the  mental  mechanism,  which  holds  these  memories  and  their  ac- 
companying charges  of  emotion,  is  called  the  unconscious,  commonly  referred 
to  as  the  unconscious  mind.  The  more  pain,  shame,  disgust  or  other  painful 
affect  that  occurs  during  development,  the  more  likely  that  repression  will  occur, 
and  the  more  difficult  it  will  be  to  recall  the  traumatic  event  in  later  life.  The 
emotions  combined  with  the  memories  and  ideas  accumulated  during  growth 
make  the  unconscious  a  dynamic  center  of  psychic  energy  rather  than  a  static 
storehouse  of  innocuous  impressions. 

Anxiety  and  the  Gastrointestinal  Tract.  —  The  digestive  processes  form  the  most 
important  phase  of  the  child's  life  during  the  first  year.  If  this  function  has 
been  exposed  to,  and  associated  with,  too  much  strife,  deprivation  or  ill  will, 
they  become  associated  in  the  mind  of  the  infant.  One  is  "conditioned"  to  the 
other.  The  memories  of  unpleasant  experiences  associated  with  the  gastroin- 
testinal function  exist  in  that  part  of  the  mind  we  call  the  unconscious.  As  the 
child  grows  older,  life  conditions  often  improve,  but  a  revival  of  the  same  situa- 
tion of  deprivation  at  the  hands  of  fate  or  ill  will  from  classmates,  business 
associates  or  spouse  may  reactivate  anxiety.  Now,  if  this  anxiety  and  its  cause 
are  recognized  and  can  be  dealt  with  through  escape,  compromise  or  sharing  with 
some  stronger  person  the  experiences  and  their  effects,  thus  gaining  reassurance 
and  new  strength,  a  solution  is  found.  If  the  anxiety  is  not  recognized  and  is 
not  adequately  discharged,  it  finds  no  release  and  must  exert  its  force  upon  the 
body  itself.  Then  some  organ  or  organ  system  is  very  apt  to  bear  the  brunt  of 
this  potent  force  and  will  function  badly  as  a  result.  If  during  the  years,  when 
the  swallowing  and  digestive  processes  are  of  paramount  importance  in  the  life 
of  the  child,  there  were  anxiety -producing  experiences,  then  similar  experiences 
later  in  life  are  likely  to  reproduce  symptoms  of  the  upper  gastrointestinal  tract. 

Organ  Neurosis.  —  With  regard  to  other  related  factors  one  may  say  that 
the  earlier  in  life  and  the  more  profound  the  psychological  traumatic  experience, 
the  more  serious  the  resulting  psychosomatic  affection  may  prove  to  be.  The 
term  organ  neurosis  is  used  frequently  to  designate  the  disturbance  in  the  work- 
ing of  a  bodily  organ  resulting  from  psychic  forces.  But  there  are  various  de- 
grees of  organ  neurosis.  Perhaps  the  most  simple  expression  of  psychological 
conflict  is  the  so-called  conversion  hysteria  in  which  the  symptom  is  the  symbolic 

Vol.  I.  445 


PSYCHOPATHOLOGY 


744  (15) 


expression  of  the  psychological  conflict.  Thus  nervous  vomiting  may  have  dis- 
gust as  one  of  its  meanings.  A  more  severe  degree  of  organ  neurosis,  or  what  is 
sometimes  referred  to  as  a  vegetative  neurosis,  is  a  disorder  in  which  actual 
physical  changes  take  place  as  a  result  of  a  profound  psychological  disturbance. 
Cardiospasm  is  an  example.  Just  as  psychosis  probably  represents  in  the  mental 
sphere  earlier  and  more  serious  emotional  traumatic  experience  than  neurosis,  so 
does  vegetative  neurosis  represent  earlier  and  more  profound  psychological  dis- 
turbance than  conversion  hysteria  so  far  as  psychosomatic  medicine  is  concerned. 
Relation  of  Symptoms  to  Life  Situation.  —  There  are  certain  epochs  in  life 
when  psychosomatic  affections  are  apt  to  make  their  appearance.  These  are 
outlined  in  Table  I. 

TABLE  I* 
Correlation  or  Life  Situation  and  Symptom  Formation 


Oral  Stage  (first  year  of  life) 

Food  and  love  are  being  given  to  the  child 
with  no  responsibilities  exacted  in  return. 


Refusal  to  nurse;  fretfulness  when  nursing  is 
over,  or  contentment?  Protest  to  weaning 
(crying  or  vomiting)? 


Anal  Period  (1-3  years) 

Responsibility  of  cleanliness  and  neatness 
has  to  be  taken  over  in  toilet  habits  and 
in  other  activities.  This  is  not  easj',  and 
the  child  needs  much  friendliness,  un- 
derstanding and  patience  to  accomplish 
it  without  anxiety  or  detriment  to  per- 
sonality development. 


Is  toilet  training  accepted,  or  is  child  stub- 
bornly resistive,  wetting  and  soiling  beyond 
usual  age  of  established  cleanliness?  Is 
there  constipation,  temper  tantrum,  stub- 
bornness, resentment,  destructiveness? 


Genital  Period  (3-6  years) 

Period  of  increasing  general  and  sexual 
curiosity.  Period  of  beginning  tender 
attachment  to  parent  of  opposite  sex. 


Excessive  masturbation,  fretfulness,  disobedi- 
ence, aggression,  cruelty,  eneuresis,  poor 
adjustment  to  other  children. 


Latent  Period  (6-12  years) 
Period  of  primary  education,  identification 
with  ideals  and  authority. 


How  is  social  adjustment?  Does  he  do  well 
in  studies?  Does  he  mix  well  in  classroom 
and  playground?  Is  there  sexual  delin- 
quency, truancy,  aggressiveness,  cruelty, 
poor  sportsmanship,  seclusiveness? 


Puberty  (12-15  years) 

Period  of  maturity  and  beginning  activity 
of  sex  glands.  Extra  impetus  given  to 
entire  emotional  life,  especially  emotional 
patterns  pertaining  to  love  and  sexuality. 

*  From  Weiss,  E.,  and  English,  O.  S. 
Vol.  I.  445 


Are  there  anxiety  attacks;  fears  of  disease, 
of  death,  of  harming  others;  nightmares, 
irritability,  social  anxiety,  seclusiveness, 
loss  of  appetite,  vomiting,  diarrhea,  cardiac 
palpitation? 

Psychosomatic  Medicine,  p.  541^". 


744  (i6) 


PSYCHOSOMATIC   MEDICINE 


TALE  I — (Continued) 


Adolescence  (15-21  years) 

Period  of  secondary  and  college  education. 
Often  the  need  to  leave  the  home  and 
live  among  strangers.  Beginning  of  love 
relationships.  Planning  for  life  work, 
career,  home,  marriage.  The  fields  of 
competition  widen.  Conflicts  over  re- 
ligion or  ideals  and  current  behavior. 


Are  there  symptoms  occurring  on  leaving 
home,  on  beginning  or  ending  a  love  affair, 
because  of  inability  to  compete?  Are  there 
seclusiveness  and  anxiety?  A  period  in 
which  the  incidence  of  somatic  symptoms 
is  high! 


Early  Adult  Life  (21-40  years) 

Decisions  must  be  made  about  love,  mar- 
riage, work,  parenthood.  Parental  sup- 
port drops  away  after  21,  if  not  before. 
Responsibilities  of  adulthood  are  thrust 
upon  one.  They  catch  up  with  one 
whether  he  is  prepared  for  them  or  not. 
May  be  stress  of  military  service. 


Symptoms  may  appear  in  relation  to  engage- 
ment, marriage,  pregnancy,  childbirth,  loss 
of  job,  failure  to  adjust  in  marriage,  or  new 
environment.    "War  neuroses". 


Middle  Adult  Life  (40-60  years) 

Period  when  anticipated  ambitions  are  lost 
or  realized.  Children  begin  to  leave 
home.  Women  go  through  menopause. 
Both  sexes  have  to  adjust  to  changing 
values. 


Women  have  to  cope  with  the  menopause  and 
loss  of  companionship  of  the  children.  May 
not  be  resourceful  enough,  become  de- 
pressed and  anxious.  For  men  it  is  the 
age  of  business  success  and  failure.  Of 
divorce.  Reactions  to  physical  disease. 
Cancerophobia,  depression  and  suicide. 


Late  Adult  Life  and  Old  Age  Period  (60  years 
plus) 
Period  of  retirement  for  men,  forced  or 
voluntary.  Dependency  on  children  for 
support  in  both  sexes.  Problems  of 
physical  disease  (geriatrics)  and  the  need 
for  care  by  others. 


Symptoms  of  anxiety  often  appear  after  re- 
tirement, and  many  symptoms  are  due  to 
the  frictions  incident  to  living  with  children 
and  in-laws.  Arteriosclerosis  and  senile 
dementia  usually  make  social  adjustment 
more  difficult. 


In  the  beginning  of  this  discussion  I  suggested  that  there  was  no  sharp  line 
between  normal  and  neurosis.  Nevertheless  there  are  certain  distinguishing  fea- 
tures, and  indeed  one  of  the  first  problems  that  presents  itself  to  the  physician 
in  dealing  with  a  patient  is  to  try  to  determine  whether  one  is  dealing  with  a 
normal,  a  neurotic  or  a  psychotic  personality.  Glover^  has  defined  the  normal 
personality  as  being  (i)  free  of  symptoms,  (2)  unhampered  by  mental  conflict, 
(3)  having  a  satisfactory  working  capacity  and  (4)  being  able  to  love  someone 
other  than  oneself.  Neurosis  and  psychosis  show  pronounced  deviations  in  each 
of  these  spheres  as  shown  in  Table  II.  * 

Vol.  I.  445 


PSYCHOPATHOLOGY 


744  (17) 


TABLE   II* 

NORMAL   PERSONALITY 

NEUROSES 

PSYCHOSES 

Emotional  Features 

Unhampered  by  men- 

Ability to  reach  a  de- 

Hampering     mental 

Mental  conflicts 

tal  conflict 

cision    without    too 

conflicts 

Severe     mood     dis- 

much stress  or  de- 

Mild  mood  disturb- 

turbances 

lay 

ances 

Capacity  for  decision 

Capacity  for  decision 

impaired 

impaired 

Satisfactory  work  ca- 

Enjoys work 

Work  not  enjoyed 

Severe    disturbances 

pacity 

No  undue  fatigue 

Fatigue    a    frequent 

in   efficiency;     con- 

No need  for  frequent 

and        pronounced 

centration  upon  or 

change 

symptom 

participation          in 

Maintains    optimum 

Impairment  work  ef- 

work   may    be    to- 

efficiency 

ficiency 

tally  impossible 

AbiUty  to  love  some- 

Takes    pleasure     in 

Disturbances           in 

Severe    disturbances 

one  other  than  self 

social  relationships. 

ability  to  enjoy  so- 

in    abiUty     to     re- 

marital       relation- 

cial   relations,    i.e., 

late    themselves    to 

ships,  parental  rela- 

inability   to    relate 

others,  in  fact,  the}' 

tionships.     Can  un- 

themselves to  others 

tend     to     renounce 

derstand    the    emo- 

in such  a  way  as  to 

their     relations     to 

tional     needs     and 

gain    security    and 

others  more  or  less 

point    of    view    of 

emotional  response. 

completely 

others  and  make  ap- 

Limited  capacity  to 

~  propria te  response 

give  emotionally ,  yet 
some     conventional 
relation  to  others  is 
maintained        even 
though       imperfect 
and  at  the  cost  of 
anxiety 

Physical  Status 

Conversion    of   emo- 

Somatic      symptom 

Absence  of  symptoms 

(of  neurotic  origin) 

tional    stress    (anx- 

formation      during 

iety)    into    somatic 

onset  of  illness,  but 

symptoms  in  one  or 

eventually       symp- 

many parts  of  body 

toms  are  in  sphere 
or         control         of 
emotion,      thought, 
speech,  action 
Varying    amount    of 
loss    in    control    of 
well          integrated 
thought,       emotion 
and  speech,  and  re- 
gressions to  childish 
levels — and/or  solu- 
tion      of       anxiety 
through  false  beliefs 
or  false  sensory  per- 
ception 

*  From  Weiss,  E.,  and  English,  O.  S.:   Psychosomatic  Medicine,  p.  42'*'. 
Vol.  I    445 


744  (i8)  PSYCHOSOMATIC   MEDICINE 

Psychosomatic  Study  in  Illness 

In  a  general  way  it  may  be  stated  that  in  addition  to  the  physical  study  the 
psychosomatic  approach  consists  in  getting  to  know  the  patient  as  a  human 
being  rather  than  as  a  mere  medical  case.  Too  often,  as  already  stated,  the 
patient  is  looked  upon  as  only  a  physiological  mechanism  and  is  studied  by 
means  of  medical  history  and  physical  examination  aided  by  "instruments  of 
precision"  and  chemical  tests.  Tape  measure  and  test  tubes  carry  the  erroneous 
notion  of  exactness  and  thoroughness,  erroneous  because  the  emotional  life  of 
the  individual,  which  may  hold  the  key  to  the  solution  of  the  problem,  is  not 
investigated  or  at  best,  inadequately  so. 

While  the  subject  cannot  be  discussed  in  detail,  usually  the  best  procedure 
in  dealing  with  these  patients  is  as  follows. 

(i)  To  satisfy  ourselves  and  establish  their  confidence,  a  thorough  medical 
history  should  be  taken ;  this  must  contain  more  information  regarding  the  family 
and  social  background  of  the  patient  than  most  of  our  present  histories  do.  Many 
years  ago  Kilgore^  criticized  the  standardization  of  hospital  clinical  records.  His 
criticism,  part  of  which  follows,  still  stands.  "The  amazing  epidemic  of  stand- 
ardization that  has  been  visited  upon  American  institutions  in  this  century  has 
not  permitted  our  clinical  records  to  escape.  In  practically  all  hospitals  with 
any  pretensions  one  finds  the  clinical  records  usually  in  trim  aluminum  covers 
with  some  variation  in  charts  and  laboratory  sheets  but  with  the  clinical  history 
proper  invariably  displayed  under  a  stereotyped  system  of  paragraphs  with  or 
without  the  guidance  of  printed  forms.  The  histories  thereby  are  given  an 
orderliness,  which  is  pleasing  to  the  eye,  and  which  makes  a  tacit  claim  to  the 
admirable  quality  of  thoroughness. 

"And  yet  these  standardized  histories  are  open  to  a  very  serious  criticism. 
My  criticism  may  be  interpreted  from  the  following  illustration:  In  a  medical 
ward  of  a  class  A  teaching  hospital  I  recently  saw  a  Jewess,  aged  forty-five  years. 
Five  minutes'  conversation  brought  out  the  facts  that  she  had  always  been  in 
reasonably  good  health  until  after  the  death  of  her  husband  a  year  ago,  that  she 
then  looked  hopefully  for  support  from  her  eldest  son,  but  that  about  three 
months  ago  she  gradually  experienced  the  final  and  crushing  conviction  that  his 
talents  were  limited  to  the  selling  of  newspapers,  which  yielded  a  profit  of  less 
than  a  dollar  a  day.  She,  therefore,  in  addition  to  caring  for  her  home  and  the 
younger  children,  took  employment  in  a  restaurant,  standing  eight  hours  a  day 
washing  dishes.  Then  came  backache,  sleepless  nights  of  worry,  anorexia,  loss 
of  20  pounds,  nervousness,  utter  exhaustion,  hospitalization.  Cursory  examina- 
tion revealed  only  the  ordinary  effects  of  such  a  life  including  possibly  some 
thyroid  disturbance. 

"Now  I  ask  of  you  sticklers  for  form  and  order,  what  do  you  suppose  that 

Vol.  I.  445 


PSYCHOSOMATIC   STUDY   IN   ILLNESS  744  (19) 

woman's  folder  contained?  Five  and  one-half  closely  written  pages  of  matter 
comprised  under  twenty-eight  captions,  all  neatly  underlined  with  red  ink  and 
ruler!  Figure  out  the  time  that  probably  took,  and  then  ask  yourselves  how 
much  time  and  energy  remained  to  devote  to  the  clinical  problem  of  that  woman. 
We  toil  through  those  five  and  one-half  pages  in  search  of  useful  bits  of  informa- 
tion. Here  and  there  we  find  a  few,  fragmentary  and  uncorrelated.  In  the  place 
for  'social  condition'  it  is  stated  that  she  is  a  widow;  under  'occupation'  that  she 
is  a  housewife;  under  'marital  history'  that  she  has  four  children,  but  not  a 
word  about  that  fiasco  of  the  eldest  son.  The  paragraph  on  'habits'  speaks  of 
weight  loss  but  gives  no  hint  of  the  possible  cause.  Breathlessly  we  work  down 
to  the  captions  'complaint',  'onset  of  present  illness'  and  'course  of  present 
illness'  and  find  only  some  sketchy  references  to  pains  in  the  back,  palpitation, 
breathlessness  on  effort,  gas  in  the  stomach  and  so  on,  but  never  a  word  of  the 
restaurant  or  the  thoughts  in  the  poor  woman's  head.  Then  comes  the  sacred 
array  of  paragraphs  on  the  various  systems  with  reiteration  of  shortness  of  breath 
under  'cardiorespiratory  system '  of  stomach  gas  under  'gastrointestinal',  etc.,  etc. 

"The  writer  of  this  history  was  evidently  painstaking  and  industrious,  and 
yet  what  a  mess  he  made  of  it!  There  is  not  the  slightest  doubt  that  if,  before 
he  ever  set  foot  in  the  medical  school,  he  had  been  confronted  with  this  patient 
and  had  been  asked  to  write  down  what  he  could  find  out  about  her  condition, 
he  would  have  done  incomparably  better.  And  as  a  commentary  on  the  teach- 
ing of  clinical  history-taking  is  not  that  the  height  of  irony?  The  reason  for 
this  enormity  is  obvious.  The  writer  of  the  history  has  been  so  occupied  in  con- 
structing and  polishing  the  frame  in  order  to  meet  the  standard  specifications 
that  he  has  been  unable  to  paint  the  picture;  indeed,  he  has  scarcely  seen  the 
patient  and  her  experiences  at  all. 

"This  case,  to  be  sure,  is  worse  than  many  of  our  hospital  clinical  histories, 
but  it  is  none  the  less  a  good  illustration  of  a  valid  general  criticism  of  unre- 
strained standardization,  namely,  stereotypism,  perfunctoriness,  mediocrity." 

(2)  After  a  medical  history,  which  takes  account  of  personal  factors  as  well 
as  "medical  facts",  we  should  make  a  complete  physical  examination  and  such 
laboratory  tests  as  are  necessary  to  exclude  physical  disease  or  to  establish  the 
precise  nature  of  the  organic  problem  and  the  amount  of  disability  which  it  in 
itself  is  capable  of  causing. 

(3)  Having  assured  the  patient  that  no  physical  disease  is  present  in  the  first 
instance,  or  that  it  is  present  to  a  certain  extent  in  the  second  group,  but  that 
the  disability  is  out  of  proportion  to  the  disease,  it  is  usually  easy  by  examples 
of  psychic  causes  for  such  physiological  disturbances  as  blushing,  gooseflesh, 
palpitation  and  diarrhea  to  make  the  patient  understand  that  a  disturbance  in 
his  emotional  life  may  be  responsible  for  the  symptoms. 

(4)  Then  important  clues  for  this  disturbance  usually  can  be  found  by  en- 
VOL.  I.  445 


744  (2o)  PSYCHOSOMATIC   MEDICINE 

couraging  a  discussion  of  problems  centering  around  vocational,  religious,  marital 
and  parent-child  relationships.  Usually  this  is  best  accomplished  indirectly  rather 
than  by  direct  questions.  The  more  one  can  persuade  such  a  patient  to  talk 
about  "his  other  troubles"  the  sooner  do  we  come  to  an  understanding  of  the 
"present  troubles".  The  greater  our  success  in  switching  the  conversation  from 
symptoms  to  personal  affairs,  the  sooner  do  we  come  into  possession  of  the  real 
problem  disturbing  the  patient.  We  are  all  familiar  with  the  patient,  who  is 
preoccupied  with  his  bowel  function  and  wants  to  talk  about  nothing  else,  whose 
whole  life  really  seems  to  surround  his  daily  bowel  movement.  It  is  the  physi- 
cian's duty  tactfully  to  switch  him  from  a  discussion  of  his  symptoms  to  a  dis- 
cussion of  his  personal  life.  Encourage  him  to  talk  about  himself  as  a  person 
rather  than  as  a  medical  case.  In  adults  domestic  problems  and  professional 
and  business  relationships  play  a  large  part  in  functional  illness.  In  young, 
unmarried  people,  family  relationships,  choice  of  a  career  and  often  religious 
and  sexual  problems  are  important  topics  for  discussion. 

Usually  one  or  more  of  three  special  fears  are  uppermost  in  the  minds  of 
such  patients.  One  of  the  Inost  common  is  fear  of  cancer,  cancerphobia.  A  great 
many  patients  think  they  have  cancer,  and  indeed  most  women  who  consult 
physicians  will  have  the  idea  at  some  time.  They  do  not  always  express  it;  in 
fact,  they  rarely  directly  express  their  cancer  fears.  They  often  disguise  it  by 
a  complaint  about  a  lump,  a  swelling  or  a  curious  sensation  in  the  abdomen  or 
breast,  and  when  they  are  assured  at  the  end  of  a  complete  physical  examination 
that  they  are  free  from  organic  disease,  they  heave  a  sigh  of  relief  and  say,  "Oh, 
I  am  so  glad  because  I  thought  I  might  have  a  cancer".  With  all  of  the  propa- 
ganda for  the  early  detection  of  cancer  these  fears  are  exaggerated,  and  I  pre- 
sume it  is  the  price  that  we  must  pay  for  instructing  people  about  cancer.  I 
am  not,  of  course,  advising  against  such  instruction;  it  is  only  that  we  must 
realize  that  we  add  to  the  apprehension  of  many  patients  by  our  emphasis  upon 
the  early  detection  of  cancer. 

Another  common  fear,  as  already  suggested,  is  the  fear  of  heart  disease.  When 
pain  in  the  precordial  region  as  well  as  rapid  beating  of  the  heart,  breathlessness 
and  fatigue  occur,  suspicion  of  heart  disease  often  arises.  If  we  remember  that 
the  pain  of  cardiac  neurosis  bears  no  definite  relationship  to  effort,  is  frequently 
described  as  sticking,  needle-like  or  soreness,  that  often  it  is  associated  with  in- 
framammary  tenderness  and  hyperalgesia,  so  that  the  pressure  of  the  stethoscope 
sometimes  elicits  it,  and  that  it  may  be  accompanied  by  a  sense  of  choking  as 
well  as  sighing  respirations,  we  will  have  no  difficulty  in  the  differential  diag- 
nosis, particularly  when  we  associate  these  symptoms  with  the  whole  picture  and 
life  situation  of  the  individual  with  cardiac  neurosis. 

(5)  The  inability  to  concentrate  often  gives  rise  to  the  fear  of  "losing  the 
mind".     Along  with  this  fear  frequently  there  are  ideas  of  suicide.     Both  are 

Vol.  I.  445 


THE  ANXIETY  ATTACK  744  (21) 

very  distressing  to  the  patient  and  usually  are  not  volunteered.  When  the  pa- 
tient is  assured  that  it  is  his  feelings  which  are  involved  and  not  his  "mind", 
and  that  the  reason  his  "memory  fails  him"  is  because  he  is  so  preoccupied  with 
concern  over  his  problems,  then  he  may  confess  his  fear  that  he  was  "losing 
his  mind"  or  his  ideas  of  doing  away  with  himself. 

Once  these  ideas  are  brought  to  the  surface  and  ventilated,  and  the  patient 
receives  sufficient  reassurance,  then  often  much  improvement  occurs.  Indeed 
the  intensity  of  the  fear  and  the  amount  of  reassurance  necessary  to  abolish  it 
serve  as  a  crude  index  to  the  depth  of  the  neurosis. 

The  Anxiety  Attack 

Quite  frequently  the  first  pronounced  evidence  of  neurosis  may  be  an  anxiety 
attack,  and  again  and  again  in  studying  the  histories  of  patients  with  chronic 
invalidism  of  emotional  origin  we  find  that  the  first  outspoken  manifestation  of 
illness  was  the  sudden  onset  of  anxiety  with  apprehension  and  dread.  There  is 
a  feeling  of  weakness,  sweating  and  a  sensation  that  something  terrible  is  about 
to  happen.  There  is  dyspnea,  palpitation  and  sometimes,  nausea.  The  attacks 
usually  last  only  a  few  minutes  and  subside  rather  quickly  but  may  last  for  an 
hour  or  more.  Weakness  and  fatigue  follow.  The  emotional  as  well  as  the  physical 
distress  is  so  marked  as  to  cause  the  patient  to  conclude  that  some  very  serious 
physical  disability  is  present.  Almost  never  does  he  conclude  that  his  difficulty 
is  emotional.  Most  people  prefer  to  think  that  physical  distress  means  physical 
disease,  and  unfortunately  physicians  too  frequently  have  assisted  them  in  this 
belief.  When  a  patient  with  an  acute  anxiety  attack  is  first  examined,  the  phy- 
sician notes  the  rapid  pulse  and  listens  to  the  pounding  heart  and  all  too  often 
permits  the  patient  to  believe  that  the  heart  is  diseased,  that  hyperthyroidism 
is  present  or  covers  his  unwillingness  to  make  a  diagnosis  of  a  psychological  dis- 
order by  using  some  such  term  as  neurocirculatory  asthenia  or  autonomic  im- 
balance. This  is  immediately  reassuring  but  ultimately  harmful.  Sedatives  are 
of  very  little  help;  if  the  anxiety  is  acute,  sedation  does  not  occur  until  the  attack 
has  spent  itself  anyhow.  To  be  consistent  one  gives  no  treatment  other  than 
personal  reassurance.  To  give  drugs  and  do  nothing  about  fear  is  to  mislead 
the  patient  into  feeling  that  his  distress  is  due  to  altered  physical  pathology 
rather  than  to  psychopathology. 

In  treating  the  personality  for  the  factors  which  produce  anxiety  we  must 
realize  that  the  patient  is  apt  to  be  an  elusive,  disinterested  individual  who, 
once  over  the  first  attack,  does  not  want  anyone  to  probe  his  feelings.  When 
he  begins  to  have  frequent  attacks  and  is  afraid  to  go  where  the  attack  may 
occur,  street,  subway,  stores,  etc.,  he  has  regressed  to  a  position  in  relation  to 
his  family  which  unconsciously  he  wishes  to  maintain.     Hence  the  cooperation 

Vol.  I.  445 


744  (22)  PSYCHOSOMATIC   MEDICINE 

of  the  family  is  necessary  to  make  him  come  to  his  physician  where  he  can  be 
apprised  of  his  real  troubles  and  learn  to  correct  them. 


Organ  Language 

A  method  of  helping  patients  to  understand  their  symptoms,  which  I  find 
useful,  is  based  upon  the  symbolism  of  symptoms.  Patients  are  told  that  if 
they  cannot  find  an  outlet  for  tension  of  emotional  origin  by  word  or  action, 
the  body  will  find  a  means  of  expressing  this  tension  through  a  kind  of  "organ 
language".  The  psychopathology  responsible  for  "organ  language"  cannot  be 
discussed  in  detail,  but  many  clinical  instances  can  be  cited. 

For  example,  if  a  patient  cannot  swallow  satisfactorily,  and  no  organic  cause 
can  be  found,  it  may  mean  there  is  something  in  the  life  situation  of  the  patient 
that  he  "cannot  swallow".  Nausea  in  the  absence  of  organic  disease  sometimes 
means  that  the  patient  "cannot  stomach"  this  or  that  environmental  factor. 
Frequently  a  feeling  of  oppression  in  the  chest  accompanied  by  sighing  respira- 
tions, again  in  the  absence  of  organic  findings,  indicates  that  the  patient  has  a 
"load  on  his  chest"  that  he  would  like  to  get  rid  of  by  talking  about  his  prob- 
lems. The  patient,  who  has  lost  his  appetite  and  as  a  consequence  has  become 
severely  undernourished,  so-called  "anorexia  nervosa",  which  in  its  minor  mani- 
festations is  such  a  common  problem,  is  very  often  emotionally  starved  before 
he  becomes  physically  starved.  When  he  learns  to  taste  life,  he  will  begin  to 
taste  food.  The  common  symptom,  fatigue,  very  often  is  due  to  emotional  con- 
flict, which  uses  up  so  much  energy  that  little  is  left  for  other  purposes.  Again 
emotional  tension  of  unconscious  origin  frequently  expresses  itself  as  muscle  ten- 
sion giving  rise  to  aches  and  pains,  and  sometimes  these  are  represented  by  sharp 
pains  such  as  atypical  neuralgia.  Thus,  we  suggest  that  atypical  neuralgia  of 
the  arm  or  face  may  be  due  to  focal  conflict  as  well  as  focal  infection.  An  ache 
in  the  arm,  instead  of  representing  the  response  to  a  focus  of  infection,  may  mean 
that  the  patient  would  like  to  strike  someone  but  is  prevented  from  doing  so  by 
the  affection  or  respect  that  is  mingled  with  his  hostility.  Itching,  for  which  no 
physical  cause  is  found,  very  often  represents  dissatisfaction  with  the  environ- 
ment which  the  individual  takes  out  upon  himself;  martyr-like  he  scratches  him- 
self instead  of  someone  else.  "All-gone"  feelings  in  the  epigastrium,  "shaky 
legs"  and  even  vertigo  are  common  physical  expressions  of  anxiety,  and  the 
anxiety  attack,  so  frequently  called  a  heart  attack,  a  gall-bladder  disturbance, 
hyperthyroidism,  neurocirculatory  asthenia,  hyperinsulinism,  etc.,  is  still  far  from 
being  understood  in  general  clinical  medicine  in  spite  of  the  fact  that  Freud^ 
described  it  more  than  forty  years  ago. 

Many  more  examples  could  be  given  but  are  unnecessary.  Only  one  more 
point  remains  before  concluding  this  part  of  the  discussion,  and  that  is  that  the 

Vol..    I.  445 


SEXUAL   FACTORS  744  (23) 

gastrointestinal  tract  is,  above  all  other  systems,  the  pathway  through  which 
emotions  are  often  expressed  in  behavior.  Why  this  is  so  becomes  apparent  in 
the  study  of  psychopathology. 

This  whole  approach  can  be  summed  up  in  the  following  fashion:  Under- 
standing illness  and  treating  sick  people  consist  of  something  more  than  a  knowl- 
edge of  disease;  they  necessitate  looking  upon  illness  as  an  aspect  of  behavior. 
It  means  that  the  nature  of  bodily  disorders  can  be  appreciated  only  when  emo- 
tional factors  are  investigated  in  addition  to  physical  factors.  Such  an  approach 
can  be  applied  to  a  wide  variety  of  ailments  and  can  be  utilized  very  generally 
in  talking  with  patients.  Nor  does  it  require  a  very  high  degree  of  intelligence 
on  the  part  of  the  patient  to  follow  this  simple  explanation.  Patients  in  the 
clinic  as  well  as  those  in  private  care  can  be  dealt  with  in  this  fashion;  they  are 
just  as  susceptible  to  these  psychosomatic  disorders. 

Sexual  Factors 

This  again  is  a  subject  that  cannot  be  treated  in  detail,  but  one  point  of 
importance  does  deserve  consideration  at  this  juncture,  and  that  is  the  relation 
of  sexuality  to  neuroses. 

Ever  since  the  introduction  of  the  epoch-making  studies  of  Freud  to  the 
problems  of  neurosis,  medicine  has  misunderstood  his  conception  of  sexuality. 
He  has  been  quoted  often  to  the  effect  that  disturbances  in  genital  activity  are 
the  sole  causes  of  the  neuroses.  This  is  very  far  from  the  truth.  It  is  rather 
that  difi&culty  in  the  sexual  sphere  appears  as  a  revealing  index  to  a  neurotic 
personality  and  can  be  looked  upon  in  that  light.  In  other  words,  in  much  the 
same  manner  that  urea  retention  serves  as  an  index  to  an  impending  uremia,  so 
do  disturbances  in  the  sexual  life  of  the  individual,  such  as  varying  degrees  of 
frigidity  in  the  female  and  varying  degrees  of  impotence  in  the  male,  serve  as 
a  reliable  index  to  the  kind  of  personality  that  is  very  apt  to  develop  a  neurosis. 
Sexual  difficulties  are  rarely  in  themselves  the  cause  of  the  kind  of  the  illness 
under  consideration;  when  they  are  important  and  the  patient  has  a  satisfactory 
relationship  to  the  physician,  sufficient  confidence  will  be  gained  eventually  to 
permit  discussion  of  these  intimate  matters.  In  women  questions  regarding 
menstruation  and  child-bearing  often  will  lead  naturally  to  such  a  discussion. 

In  this  connection  let  me  suggest  a  cautious  attitude  in  regard  to  marital 
maladjustments,  which  are  often  in  the  background  of  obscure  illnesses.  The 
better  these  problems  are  understood  from  the  standpoint  of  personality  study, 
the  clearer  it  becomes  that  serious  emotional  maladjustment  is  behind  the  marital 
problem.  Consequently,  casually  to  give  advice  regarding  marriage  and  child- 
bearing,  divorce  and  extramarital  relationships  as  short  cuts  to  involved  emo- 
tional problems  is  to  assume  knowledge  beyond  present  human  understanding. 

Vol.  I.  445 


744  (24)  PSYCHOSOMATIC   MEDICINE 

Psychotherapy 

And  now  to  come  to  a  question  frequently  raised  regarding  these  matters; 
"Suppose  you  do  find  something  of  importance  in  the  emotional  life  of  a  patient, 
some  conflict  that  is  causing  illness;  What  good  does  it  do  the  patient  to  know? 
What  can  you  do  about  it?" 

First  of  all,  it  is  often  a  great  help  to  the  patient  to  know  that  the  ailment 
is  not  organic  but  is  due  to  a  disturbance  in  his  emotional  life.  When  a  neurotic 
symptom  is  divorced  from  a  fear  of  organic  disease,  cancer,  for  example,  it  loses 
its  force,  whereupon  the  slogan  "carry  on  in  spite  of  symptoms"  often  helps 
the  patient  a  great  deal.  This  is  especially  true,  if  the  psychological  approach, 
which  we  have  discussed,  is  a  part  of  the  study,  and  the  emotional  background 
of  the  illness  is  made  clear  to  the  patient. 

What  Is  Psychotherapy? 

What,  indeed,  is  psychotherapy?  Too  often  it  is  assumed  to  be  something 
vaguely  referred  to  as  "the  application  of  the  art  of  medicine".  This  defies 
analysis  but  seems  to  represent  a  combination  of  the  experience  and  common 
sense  of  the  seasoned  practitioner,  an  intuitive  knowledge  of  people,  the  cultiva- 
tion of  a  charming  bedside  manner,  such  trifles  as  serving  food  in  attractive  dishes 
and  the  generous  use  of  reassurance.  The  psychological  approach  in  medicine, 
essential  for  psychotherapy,  consists  of  something  more.  It  is  a  medical  discipline 
to  an  equal  degree  with  internal  medicine  itself.  It  is  an  effort  to  understand  the 
personality  structure  of  patients,  the  mental  mechanisms  which  are  at  work  and  the 
specific  relationships  of  psychological  situations  in  the  precipitation  of  the  illness. 

Reassurance,  in  the  majority  of  instances,  unless  combined  with  an  analysis 
of  the  illness  from  the  standpoint  of  the  behavior,  gives  only  temporary  help 
and  depending  upon  the  degree  of  anxiety  has  to  be  repeated  constantly,  like 
a  dose  of  digitalis  in  a  failing  heart.  Closely  allied  to  reassurance  is  another' 
superficial  treatment  that  rarely  results  in  more  than  temporary  help,  i.e.,  en- 
vironmental manipulation,  without  any  attempt  to  give  the  patient  insight  into 
his  conflicts. 

Real  psychotherapy,  which  is  directly  the  opposite  of  simple  reassurance, 
tries  to  make  the  patient  understand  the  meaning  of  his  symptoms  and  the  nature 
of  his  conflicts.  It  is  a  process  of  reeducation  and,  when  properly  done,  leads 
to  sufflcient  emotional  development  so  that  the  necessity  for  symptom  formation 
is  abolished.  The  best  example  of  this  kind  of  psychotherapy  is  psychoanalysis, 
but  for  various  reasons  this  method  cannot  be  applied  directly  to  the  majority 
of  patients.  Nevertheless,  psychoanalytic  insight  and  guidance  prove  adequate 
to  handle  the  emotional  factor  in  the  majority  of  psychosomatic  disturbances. 

Vol.  I.  445 


PSYCHOTHERAPY  744  (25) 

Between  simple  reassurance  at  one  end  of  the  scale  and  adequate  psychoanalysis 
at  the  other  there  are  all  degrees  of  psychotherapy,  which  can  be  applied  de- 
pending upon  the  degree  of  illness  and  the  circumstances  of  the  patient. 

It  is  my  hope  that  every  physician  will  be  trained  in  psychological  medicine 
so  that  he  may  be  able  to  understand  and  manage  the  many  emotional  problems 
that  are  presented  to  him  daily.  It  is  possible  that  some  internists  will  wish  to 
perfect  themselves  in  psychosomatic  medicine  in  the  same  way  that  others  in- 
terest themselves  chiefly  in  cardiology,  gastroenterology  and  other  fields.  Cer- 
tainly better  training  facilities  should  be  developed  for  residents  in  medicine 
to  acquire  the  psychosomatic  approach  to  medical  problems.  At  the  same  time 
an  opportunity  for  residents  in  psychiatry  to  have  more  medical  training  would 
do  a  great  deal  to  break  down  the  false  alignment  between  psychiatry  and  medi- 
cine. It  would  provide  us  with  capable  teachers,  who  could  cooperate  in  giving 
medical  students  the  psychosomatic  point  of  view.  Therein  lies  our  hope  for 
an  important  development  in  medicine.  As  a  part  of  this  process  and  essential 
for  its  development  general  hospitals  must  establish  divisions  for  the  observa- 
tion and  treatment  of  psychoneurotic  and  psychosomatic  problems.  The  time 
has  passed  for  psychiatry  to  lead  an  isolated  existence.  Until  it  is  brought  into 
physical  proximity  with  general  medicine  it  cannot  achieve  final  integration  into 
the  body  of  medical  knowledge. 

Major  and  Minor  Psychotherapy 

A  considerable  number  of  the  patients,  whom  we  have  been  considering, 
cannot  be  sent  to  psychiatrists,  nor  is  it  necessary.  Not  that  there  is  anything 
reprehensible  about  consulting  a  psychiatrist,  this  too  is  a  problem  of  education, 
but  there  are  not  enough  psychiatrists  to  take  care  of  the  thousands  of  patients, 
and  moreover,  as  I  have  tried  to  show,  a  great  part  of  this  work  lies  in  the  field 
of  general  medicine.  Another  way  of  stating  the  problem  is  to  say  that  there 
is  a  major  and  a  minor  psychotherapy  just  as  there  is  a  major  and  a  minor  surgery. 
Many  physicians,  who  practice  general  medicine,  feel  themselves  capable  of  doing 
minor  surgery,  but  only  a  few  have  the  skill  to  attempt  major  surgery.  They 
would  not  permit  themselves  to  attempt  something  for  which  they  are  not  pre- 
pared. This  is  just  as  true  in  regard  to  psychotherapy.  The  general  physician 
must  be  able  to  treat  the  minor  ailments,  but  he  must  be  able  also  to  recognize 
when  the  problem  is  beyond  him,  and  then  refer  the  patient  elsewhere  for  major 
psychotherapy.  Such  knowledge  and  such  an  approach  frequently  will  save  the 
patient  from  unnecessary  troublesome  and  expensive  medical  or  surgical  treatment 
with  a  resulting  further  degree  of  invalidism.  So  much  for  some  of  the  more  ob- 
vious benefits  to  be  achieved  by  the  psychosomatic  approach.  But  as  a  part  of 
what  is  intended  as  a  practical  introduction  to  psychosomatic  medicine  a  word 
must  be  said  about  the  cost  of  psychotherapy. 

Vol.  I.  44 T 


744  (26)  PSYCHOSOMATIC   MEDICINE 

Cost  of  Psychotherapy 

What  about  the  question  of  time,  effort  and  the  expense  of  psychotherapy? 
True  it  is  that  all  of  this  takes  time  and  effort  and  must  be  paid  for,  yet  when  we 
look  into  the  time,  effort  and  expense  that  have  been  expended  by  many  patients 
or  by  institutions  taking  care  of  these  patients  in  the  usual  medical  approach, 
we  realize  that  an  hour  or  two  well  spent  in  a  discussion  of  the  life  situation  of 
such  patients  would  obviate  a  great  deal  of  this  expense.  It  is  amazing  what 
the  total  expense  of  a  great  many  of  these  unnecessary  studies  amounts  to  so 
far  as  the  institution  is  concerned,  and  of  course  the  same  thing  is  true  in  the 
case  of  private  patients.  The  day  is  close  at  hand,  when  we  will  regard  some  of 
these  thick-chart  patients,  this  polyphysical  approach,  with  the  same  amuse- 
ment and  disdain  with  which  we  now  regard  the  polypharmacy  of  a  bygone  age 
in  medicine.  Hospitals  are  beginning  to  understand  that  it  is  not  only  intelligent 
but  economical  to  utilize  the  service  of  a  psychiatrist  in  the  general  medical 
division,  and  this  same  idea  could  be  applied  with  great  benefit  to  the  much 
discussed  medical  insurance  plans.  To  quote  Dunbar^  on  this  subject;  "Although 
the  psychic  factor  is  more  regularly  overlooked  in  the  case  of  severe  somatic 
damage  .  .  .,  and  in  the  handling  of  convalescence  and  chronic  illness,  it  is  no  less 
important  in  our  failures  —  patients  who  wander  from  physician  to  physician 
and  clinic  to  clinic.  If  a  patient  has  received  treatment  from  a  dozen  or  two  pri- 
vate physicians  and  half  a  dozen  clinics  and  has  submitted  to  elaborate  and 
expensive  laboratory  procedures  in  each  place,  one  may  be  justified  in  suspecting 
that  his  physicians  have  in  some  way  failed  to  find  out  what  was  the  matter. 
Usually  when  this  happens  it  is  because  a  prominent  psychic  factor  is  present. 
Such  patients  are  a  real  drain  on  hospital  and  clinic  time  and  funds.  They  can 
be  effectively  treated  only  if  equal  attention  is  given  to  the  psychic  and  somatic 
aspects  of  their  illness. 

"There  is  need  of  an  adequate  basis  for  the  inclusion  of  attention  to  the  psychic 
component  in  illness  in  our  public  health  program.  Its  inclusion  is  exigent,  both 
because  of  the  facts  just  stated  and  in  view  of  the  problems  of  health  insurance 
and  socialized  medicine  with  which  we  are  confronted.  A  major  weakness  of 
such  systems  as  are  in  operation  results  from  a  lack  of  knowledge  concerning 
emotions  and  physiological  changes.  ...  It  is  chronic  illness  as  well  as  those 
illnesses  which  have  the  greatest  tendency  to  become  chronic  in  which  the  psychic 
component  is  of  the  greatest  significance  to  therapy." 

Summary 

The   main   point    of   this   discussion   can   be  stated  briefly;  the  study  and 
treatment  of  illness  constitutes  much  more  than  the  investigation  and  eradica- 
VoL.  I.  445 


BIBLIOGRAPHY  744  (27) 

tion  of  disease.  Yet  there  is  nothing  new  or  startling  in  this  viewpoint.  We 
have  heard  a  great  deal  in  recent  years  about  the  study  of  the  organism-as-a-whole, 
but  for  most  part  we  have  been  paying  only  lip  service  to  this  concept.  We 
have  been  led  to  believe  that  the  art  of  the  physician,  having  to  do  with  his 
common  sense  or  intuition,  as  opposed  to  his  science,  is  sufficient  to  grasp  the 
problems  that  we  have  been  considering.  It  is  not  enough.  A  real  understandmg 
of  psychopathology  is  necessary  in  order  to  study  the  emotional  life  m  relation 
to  ill  health  In  other  words,  the  physician  must  be  able  to  define  the  specific 
mental  factors  producing  the  illness,  rather  than  to  be  satisfied  with  vague 
generalizations  about  "neurogenic  background".  Just  as  we  would  criticize  the 
physician  of  today,  who  would  call  all  fevers  malaria,  so  we  must  criticize  the 
physician  of  tomorrow,  who  hints  vaguely  at  nervous  factors  in  the  background 
of  an  illness  and  makes  no  effort  really  to  understand  the  psychic  situation. 

In  his  "History  of  Medicine"  Garrison  states  that  the  fundamental  error  of 
medieval  medical  science,  as  originally  pointed  out  by  Guy  de  Chauliac  and  elu- 
cidated by  Allbutt,  was  in  the  divorce  of  medicine  from  surgery.  He  might  have 
added  that  the  fundamental  error  of  modern  medical  science  has  been  in  the 
divorce  of  both  from  psychiatry. 

BIBLIOGRAPHY 

1.  HAMMAN,  L.:  Relationship  of  psychiatry  to  internal  medicine,  Ment.  Hyg.,  1939. 

XXIII   177 

2.  ALLBUTT,  T. C:  Visceral  Neuroses,  p.  17,  P-  Blakiston's   Son   and   Co.,  Phila- 

delphia, 1884.  .        r      1 

3.  MACY,  J.  W.  and  ALLEN,  E.  V.:  Justification  of  diagnosis  of  chronic  nervous 

exhaustion,  Ann.  Int.  Med.,  1934,  VII,  861.  ,  ^      ^  vtv     a. 

4   HALLIDAY  J  L.:  Principles  of  etiology,  Brit.  Jour.  Med.  Psych.,  1943,  XIX,  367. 
5'.  GLOVER,  E.:  Medico-psychological  aspects  of  normality,  Brit.  Jour.  Psychol., 

i9?2,  XXIII,  152.  ^  A        A/r  ^ 

6.  KILGORE,  E.  S.:  Clinical  records;  criticism  of  present  vogue.  Jour.  Am.  Med. 

7.  FREUD?s':^SlS  Papers,  Vol.  I,  p.  76,  Internat.  Psychoanalyt.  Press,  New 

8.  DUNBAr!^K:'  Psychosomatic  Diagnosis,  pp.  696-697,  Paul  B.  Hoeber,  Inc.,  New 

9.  DUNBArI'^R:'  Emotions  and  Bodily  Changes,  Columbia  University  Press,  New 

10.  WEISS,  K^^nd  ENGLISH,  O.  S.:  Psychosomatic  Medicine,  W.  B.  Saunders  Co., 
Philadelphia,  1943- 
April  I,  1945-  •  - 

Vol.  I.  445 


CHAPTER    XXI 
PHYSICAL   MEDICINE 

By    frank    H.    KRUSEN 

Table  of  Contents 

Local  Application  of  Heat 747 

Methods  of  Applying  Heat  Locally 747 

Conductive  Heat 747 

Convective  Heat 752 

Physical  Principles  Concerned  in  Local  Application  of  Heat     .      .      .  759 

Action  and  Uses  of  Local  Heating  Devices 760 

Contraindications  to  Local  Application  of  Heat 763 

Summary  of  Data  on  Local  Heat  Applications 764 

Bibliography  of  Local  Heat  Applications 764 

General  Application  of  Heat 766 

Methods  of  Producing  General  Heating  of  Body  (Fever  Therapy)      .  766 

Physical  Principles  Concerned  in  General  Application  of  Heat  771 
Action  and   Uses  of   Devices  for  General  Application  of   Heat  (Fever 

Therapy) 772 

Contraindications  to  General  Applications  of  Heat  (Fever  Therapy)  .  780 

Summary  of  Data  on  Fever  Therapy 781 

Bibliography  of  Fever  Therapy         782 

Local  and  General  Applications  of  Cold 785 

Methods  of  Applying  Cold 785 

Physical  Principles  Concerned  in  Application  of  Cold 787 

Action  and  Uses  of  Cooling  Procedures 787 

Contraindications  to  Applications  of  Cold 791 

Summary  of  Data  on  Cold  Applications 792 

Bibliography  of  Cold  Applications 792 

Ultraviolet  Radiant  Energy 793 

Methods  of  Applying  Ultraviolet  Radiant  Energy 793 

Physical   Principles  Concerned   in   Application  of  Ultraviolet  Radiant 

Energy 799 

Action  and  Uses  of  Ultraviolet  Radiant  Energy 800 

Contraindications  to  Application  of  Ultraviolet  Radiant  Energy    .      .  810  (7) 

Summary  of  Data  on  Radiant  Energy 810  (7) 

Bibliography  of  Radiant  Energy 810  (8) 

Hydrotherapy 810  (9) 

Methods  of  Applying  Hydrotherapy 810  (9) 

Physical  Principles  Concerned  in  Employment  of  Hydrotherapy    .      .  810  (13) 

Action  and  Uses  of  Hydrotherapy 810  (14) 

COPYRIGHT   1941   BY  THE  OXFORD   UNIVERSITY   PRESS,   NEW   YORK.   INC. 

745 


746  PHYSICAL    MEDICINE 

Contraindications  to  Employment  of  Hydrotherapy 8io  (17) 

Summary  of  Data  on  Hydrotherapy 810  (iS) 

Bibliography  of  Hydrotherapy 810  (18) 

Electrotherapy 810  (20) 

Constant  Current 810  (20) 

Methods  of  Applying  Constant  Current 810  (20) 

Physical  Principles  Concerned  in  Therapeutic  Application  of  Con- 
stant Current 810  (22) 

Action  and  Uses  of  Constant  Current 810  (22) 

Contraindications  to  Employment  of  Constant  Current      .      .      .  810  (24) 

Summary  of  Data  on  Constant  Current 810  (24) 

Faradic  Current 810  (24) 

Methods  of  Applying  Faradic  Current 810  (25) 

Physical   Principles   in   Therapeutic   Application   of  Faradic  Cur- 
rent        810  (25) 

Action  and  Uses  of  Faradic  Current .810  (27) 

Contraindications  to  Use  of  Faradic  Current 810  (28) 

Summary  of  Data  on  Faradic  Current 810  (28) 

Interrupted  Galvanic  and  Sinusoidal  Currents 810  (28) 

Methods  of  Applying  Interrupted  Galvanic  and   Sinusoidal   Cur- 
rents      810  (29) 

Physical  Principles  Concerned  in  Application  of  Interrupted  Gal- 
vanic and  Sinusoidal  Currents 810  (29) 

Actions  and  Uses  of  Interrupted  Galvanic  and  Sinusoidal  Currents  810  (30) 
Contraindications    to   Application   of    Interrupted    Galvanic   and 

Sinusoidal  Currents    .          810  (32) 

Summary  of  Data  on   Interrupted  Galvanic  and  Sinusoidal  Cur- 
rents      810  (32) 

Diathermy 810  (32) 

Methods  of  Applying  Diathermy 810  (34) 

Physical  Principles  Concerned  in  Application  of  Diathermy    .      .  810  (36) 

Actions  and  Uses  of  Diathermy 810  (37) 

Contraindications  to  Employment  of  Diathermy 810  (39) 

Summary  of  Data  on  Diathermy 810  (39) 

Bibliography  of  Electrotherapy 810  (40) 

Massage 810  (42) 

Methods  of  Applying  Massage 810  (42) 

Physical  Principles  Concerned  in  Application  of  Massage    .      .      .      .  810  (44) 

Action  and  Uses  of  Massage 810  (44) 

Contraindications  to  Application  of  Massage 810  (49) 

Summary  of  Data  on  Massage 810  (49) 

Bibliography  of  Massage 810  (49) 

Corrective  or  Therapeutic  Exercise 810  (51) 

Methods  of  Applying  Therapeutic  Exercise 810  (51) 

Physical  Principles  Concerned  in  Application  of  Therapeutic  Exercise  810  (52) 

Action  and  Uses  of  Therapeutic  Exercise 810  (53) 

Contraindications  to  Employment  of  Therapeutic  Exercise.      .      .      .  810(56) 

Summary  of  Data  on  Therapeutic  Exercise 810  (56) 

Bibliography  of  Therapeutic  Exercise 810  (56) 

Vol.  I.  941 


METHODS  OF  APPLYING  HEAT  LOCALLY  747 

LOCAL  APPLICATION  OF   HEAT 

The  application  of  heat  locally  is  one  of  the  most  common  procedures 
in  the  practice  of  medicine.  Heat  may  be  applied  by  conduction,  con- 
vection or  conversion.  The  application  of  conductive  heat  by  direct 
application  of  water  is  discussed  later  in  the  section  on  Hydrotherapy. 
The  procedures  for  applying  conversive  heat  locally  are  described  in  the 
section  on  Electrotherapy.  The  majority  of  the  methods  of  applying  con- 
ductive heat  and  the  procedure  for  application  of  convective  heat  are 
considered  here. 

Conductive  heating  can  be  accomplished  by  the  direct  application  of  a 
warm  object  to  a  bodily  surface.  Conductive  heating  devices  can  be 
heated  by  means  of  (i)  warm  air,  (2)  warm  water,  (3)  chemicals  or 
(4)  electrical  resistance  coils.  Previously  heated  solids  or  semisolids  also 
can  be  employed  for  conductive  heating. 

Convective  heating  usually  is  accomplished  by  reflection  of  infra-red 
or  luminous  radiant  energy  on  some  region  of  the  body. 

Methods  of  Applying  Heat  Locally 
Conductive  Heat 

Warm  Air  Devices.  —  Hot  air  chambers,  blowers  or  applicators  heated 
from  within  by  means  of  hot  air  have  been  used  medically.  Hot  air 
chambers  (Fig.  i),  constructed  of  wood  or  metal  and  lined  with  asbestos, 
were  developed  by  August  Bier^  and  described  by  Willy  Meyer-  more 
than  forty  years  ago.  Although  such  chambers  have  been  abandoned  to 
a  large  extent  in  this  country,  they  still  are  employed  enthusiastically  by 
South  American  and  Italian  physicians.  The  chambers  have  an  opening 
at  one  end  to  permit  the  insertion  of  an  arm  or  leg.  Usually  they  are 
heated  by  an  alcohol  lamp  or  by  a  can  of  solidified  alcohol.  The  air  within 
the  chamber  usually  is  extremely  hot,  attaining  a  temperature  of  250°  to 
260°  F.  (121°  to  125°  C). 

Recently  the  Council  on  Physical  Therapy  of  the  American  Medical 
Association  approved  a  device  which  circulates  warm  air  within  a  sleeve 
fastened  to  an  extremity.  An  apparatus  which  circulates  hot  air  within  a 
distensible  rubber  bag  also  is  being  recommended  currently.  The  bag  is 
inserted  into  the  vagina  for  treatment  of  pelvic  inflammatory  disease. 
The  pressure  usually  is  i  to  i|  pounds  (0.5  to  0.7  kg.)  and  the  tempera- 
ture not  more  than  130°  F.  (54.4°  C.)^ 

Warm   Water  Devices.  —  The  time-honored  hot  water  bottle  falls  in 

Vol.  I.  941 


748  PHYSICAL   MEDICINE 

this  category  as  does  the  so-called  Elliott  treatment  regulator.     The  hot 
water  bottle  is  sufficiently  well  known  to  preclude  the  necessity  of  careful 


Fig.  I.  A  hot  air  chamber  for  local  application  of  heat.  Although  still  employed 
enthusiastically  in  some  parts  of  the  world,  in  the  United  States  this  device  now  has 
become  almost  obsolete. 

description.     Recently  an  electrical  immersion  heater  has  been  developed 
which  can  be  inserted  in  the  standard  hot  water  bottle  in  place  of  the 
Vol.  I.  941 


METHODS  OF  APPLYING   HEAT  LOCALLY  749 

usual  cap.  Its  purpose  is  to  maintain  the  temperature  of  the  water  within 
the  bag  at  a  constant  level. 

The  Elliott  apparatus  heats  and  circulates  water  which  is  passed  under 
pressure  through  thin  rubber  applicators.  These  applicators  are  con- 
structed for  insertion  into  various  bodily  orifices. 

Chemical  Devices.  —  Pads  which  make  use  of  the  latent  heat  of  crystal- 
lization to  produce  prolonged  heating  effects  have  been  employed  thera- 
peutically. These  pads  have  been  constructed  for  application  to  the  eye'*, 
to  the  frontal  region^  or  to  other  regions  of  the  body^.  One  type^-  ^  of 
chemical  heating  pad  contains  sodium  acetate  90.5  per  cent.,  glycerin  3 
per  cent.,  sodium  sulfate  crystals  2  per  cent,  and  anhydrous  sodium  sul- 
fate 4.5  per  cent.  These  chemicals  are  sealed  inside  the  rubber  applicator 
which  is  boiled  for  ten  minutes  before  use.  The  pad  then  will  remain  at  a 
temperature  of  about  108°  to  114°  F.  (42.2°  to  45.5°  C.)  for  approximately 
an  hour.     It  has  a  lifetime  of  about  600  hours  of  service. 

The  other  type  of  chemical  heating  pad"  depends  on  the  chemical  reac- 
tion which  occurs  when  water  is  added  to  a  mixture  of  finely  divided  iron 
84  per  cent.,  sodium  chloride  6  per  cent,  and  manganese  dioxide  10  per 
cent.  The  chemicals  are  placed  in  a  canvas  bag  enclosed  in  flexible 
rubber.  If  2  drachms  (7.5  c.c.)  of  water  are  placed  inside  the  container, 
heat  will  be  liberated.  After  use,  if  the  cover  is  removed,  it  will  cool 
rapidly.     It  has  a  useful  life  of  80  to  125  hours. 

Devices  Containing  Electrical  Resistance  Coils.  —  Pads  containing  elec- 
trical resistance  coils  with  a  flexible  insulated  covering  are  used  commonly 
today.  In  fact,  they  have  become  household  utility  devices.  Such  pads 
are  not  satisfactory  for  therapy.  They  tend  to  become  too  hot;  tempera- 
ture control  is  inadequate,  and  the  fact  that  they  produce  burns  or  shocks 
occasionally  is  reported. 

Electrical  pads  which  can  be  controlled  more  accurately  than  the 
household  heating  pad  have  been  constructed  for  therapeutic  use.  One 
such  device^  consists  of  a  flat  coil  contained  in  a  waterproof  cover.  A 
thermostat  of  considerable  accuracy  permits  minute  adjustments  of  tem- 
perature. A  mercury  thermometer,  inserted  in  a  pocket  in  the  cover, 
allows  close  observation  of  the  temperature.  The  pad  is  intended  to  be 
used  for  the  purpose  of  keeping  hot  moist  dressings  at  a  constant  tem- 
perature. 

Parts  of  an  electrically  heated  suit,  similar  to  those  worn  by  deep  sea 
divers  and  stratosphere  fliers,  have  been  employed  therapeutically  for 
local  application  of  heat  to  a  certain  region  of  the  body.  Brown  and 
AUen^  used  cuff's  or  sleeves  of  this  sort  in  treatment  of  peripheral  vascular 
diseases.     Recently  I  have  had  constructed  a  device  of  this  type  for  appli- 

VOL.  I.  941 


750 


PHYSICAL   MEDICINE 


cation  of  conductive  heat  to  the  shoulder  and  upper  part  of  the  arm 
(Fig.  2).  It  has  the  advantage  of  providing  uniform  heating  of  all  the 
surfaces  of  the  shoulder  and  arm  surrounded  by  it.  All  or  any  part  of  an 
electrically  heated  suit  thus  can  be  constructed  so  that  regulated  conduc- 
tive heat  can  be  applied  to  all  sides  of  various  regions  of  the  body. 

Recently  an  ingenious  electric  blanket  (Fig.  3)  has  been  developed; 
this  was  intended  primarily  for  household  employment  but  may  be  found 
extremely  useful  in  medical  practice^.     A  transformer  within  the  control 


Fig.  2.  A  new  type  of  electrically  heated  shoulder  and  arm  pad  with  an  accurate 
thermostatic  control.     It  has  the  advantage  of  providing  uniform  heating  of  all  surfaces. 

box  reduces  the  usual  115  volt  current  to  18  volts  at  the  blanket.  This 
practically  eliminates  the  danger  of  electrical  shock.  A  thermostat  in  the 
control  box  can  be  adjusted  manually  to  the  desired  level  of  temperature. 
It  then  will  maintain  this  level  despite  changes  in  the  temperature  of  the 
room.  If  the  environmental  temperature  rises,  the  blanket  will  cool,  and 
conversely,  if  the  room  becomes  cool,  the  blanket  will  warm  up  until  the 
predetermined  level  is  reached. 

This  type  of  blanket  should  prove  valuable  for  maintenance  of  a  con- 
stant, optimal  bodily  temperature  in  certain  cases  of  peripheral  vascular 
disease.  It  might  prove  valuable  also  for  keeping  tuberculous  patients 
at  a  constant  comfortable  warmth  while  sleeping  in  well  ventilated  rooms 

Vol.  I.  941 


METHODS  OF   APPLYING   HEAT   LOCALLY 


751 


during  cold  weather.  Likewise,  it  should  be  valuable  in  providing  a  safe 
type  of  warm  bed  to  combat  postoperative  surgical  shock.  There  would 
not  be  the  danger,  which  has  been  observed  so  often  in  the  past,  of  burn- 
ing semiconscious  patients  with  hot  water  bottles. 

Previously  Heated  Solids  and  Semisolids.  —  The  ancient  household 
custom  of  applying  hot  irons,  hot  bricks,  hot  salt  bags  or  hot  sand  bags 
to  various  regions  of  the  body  for  relief  of  pain  or  of  muscular  spasm  has 
declined  recently.    This  is  largely  because  of  the  fact  that  the  temperature 


Fig.  3.  An  automatic  electric  blanket,  the  temperature  of  which  can  be  adjusted  to 
the  desired  level.  This  temperature  is  maintained  by  means  of  a  thermostat  despite 
changes  in  environmental  temperature  (From  Krusen,  F.  H.:  Physical  Medicine,  Saunders, 
Philadelphia,   1941). 


of  the  simple  devices  of  a  similar  nature,  which  are  now  readily  available, 
can  be  controlled  more  accurately. 

The  employment  of  hot  mud  packs  has  been  popularized  commercially 
by  certain  European  spas.  The  claims  for  alleged  specific  effects  of 
various  types  of  "therapeutic"  muds  have  been  vague  and  completely 
unconvincing.  Typical  examples  of  this  kind  of  supposedly  therapeutic 
mud  are  the  "piestany"  mud  and  the  "fango"  mud.  There  is  no  con- 
vincing evidence  that  such  nmds  contain  constituents  which  enhance  their 
effectiveness  when  they  are  applied  to  the  surface  of  the  body. 

Working  in  my  department,  R.  L.  Bennett  checked  the  action  on 
photographic  paper  of  the  allegedly  radioactive  "fango"  mud.  He  found 
that  there  was  insufficient  radioactivity  to  fog  the  paper,  even  after 
exposure    for    twenty-four    hours.      It  was  concluded    that    the    supposed 

Vol.  I.  941 


752  PHYSICAL   MEDICINE 

radioactivity  would  have  a  negligible  therapeutic  effect.  In  addition, 
comparative  clinical  tests  were  performed  which  revealed  no  essential 
differences  between  the  thermal  effects  of  "fango"  mud,  ordinary  garden 
mud  and  Mississippi  valley  clay.  It  would  seem  that  "therapeutic" 
muds  have  no  particular  advantage  over  simpler  and  cleaner  methods  of 
applying  heat. 

Hot  paraffin  can  be  applied  easily  to  local  regions  and  is  clean  and 
effective.  All  the  materials  which  are  necessary  are  "jelly  wax"  or  or- 
dinary commercial  paraffin,  a  kitchen  stove  and  a  double  boiler,  such  as 
can  be  found  in  any  kitchen.  I  frequently  recommend  that  paraffin  be 
employed  for  local  application  of  heat  when  the  patient  lives  in  a  house 
which  is  not  equipped  with  electricity  to  operate  a  homemade  baker  or  a 
simple  heat  lamp.  But  even  in  well-supplied  institutions  paraffin  fre- 
quently is  employed  in  preference  to  other  local  heating  measures.  The 
paraffin  is  placed  in  the  inner  pan  of  the  double  boiler,  and  water  is 
poured  into  the  outer  pan.  The  boiler  then  is  placed  on  the  stove  and 
heated  until  all  the  paraffin  has  melted.  It  is  permitted  then  to  cool 
until  a  thin  film  of  solidifying  paraffin  has  formed  on  the  surface.  At 
this  time  the  paraffin  will  be  at  its  low  melting  point  which  is  approxi- 
mately 167  °  to  176°  F.  (75°  to  80°  C). 

The  parafifin  then  is  painted  over  the  region  which  is  to  be  treated. 
About  a  dozen  coats  are  applied  in  rapid  succession.  The  layers  of  paraf- 
fin solidify  almost  instantly  to  form  a  thick  warm  covering  of  the  surface. 
This  covering  is  left  in  place  for  at  least  thirty  minutes.  Variations 
include  dipping  of  a  part,  usually  a  hand  or  foot,  in  the  paraffin  about 
six  times  to  form  a  similar  warm  parafifin  pack,  applying  alternate  layers 
of  bandage  and  paraffin  to  a  joint  to  provide  a  warm  firm  supporting 
dressing,  or  leaving  the  part  immersed  in  a  special  large  parafifin  bath  for 
thirty  minutes  or  longer. 

I  have  placed  thermocouples  beneath  parafifin  packs  or  dressings  and 
have  found  that  the  temperature  is  kept  above  normal  levels  for  more 
than  an  hour. 

Convective  Heat 

Convective  heating  is  accomplished  by  irradiation  of  the  surface  of  the 
body  with  rays  from  the  visible  and  infra-red  regions  of  the  electromag- 
netic spectrum.  A  beam  of  visible  light  can  be  split  by  means  of  a 
triangular  prism  into  the  various  colors  of  the  rainbow.  Above  the 
violet  end  of  this  rainbow  are  situated  the  invisible  ultraviolet  rays;  below 
the  red  end  lie  the  invisible  infra-red  or  heat  rays. 

Vol.  I.  941 


METHODS  OF  APPLYING   HEAT  LOCALLY  753 

A  variety  of  infra-red  generators  has  been  marketed  for  therapeutic 
use.  The  units  commonly  employed  at  present  consist  of  a  spiral  coil  of 
resistant  metal  wire  wound  around  a  cone  made  of  steatite  or  porcelain,  or 
plates,  rods  or  disks  of  resistant  metal  such  as  carborundum.  These  units 
usually  are  placed  in  a  cup-shaped  reflector  which  will  cause  the  rays  to 
converge  on  the  part  which  is  to  be  treated  (Fig.  4).     The  infra-red  lamp 


Fig.  4.     An   infra-red   unit,  nonlumlnous  variety,   in   the   usual   type  of  cup-shaped 
reflector  which  causes  the  radiation  to  converge  to  a  focal  point. 


employed  by  the  physician  dififers  little  from  the  familiar  household  electric 
heater  (Fig.  5).  The  chief  difference  is  in  the  shape  of  the  reflector.  The 
household  heater  has  a  flatter,  platelike  reflector,  which  diffuses  the  heat 
rays  through  the  room,  while  the  infra-red  lamp  has  a  more  concave,  cup- 
shaped  reflector,  which  concentrates  the  rays  on  a  small  local  region.  The 
heating  units  themselves  can  be  used  interchangeably  because  the  ra- 
diation from  one  is  practically  identical  with  that  from  the  other. 

It  is  obvious,  therefore,  that  infra-red  rays  are  not  mysterious  or  un- 
usual.    However,  even  though  infra-red  rays  simply  are  heat  rays,  they 

Vol.  I.  941 


754 


PHYSICAL   MEDICINE 


are,  nevertheless,  of  considerable  usefulness  in  therapy.  For  many  years 
illumination  engineers  have  known  that  radiation  from  luminous  sources, 
such  as  tungsten  or  carbon  filament  bulbs,  penetrates  human  tissues  to  a 
greater  depth  than  that  from  nonluminous  sources  such  as  the  infra-red 
coils  or  plates.  Oddly  enough,  physicians  have  not  been  familiar,  as  a 
rule,  with  this  fact.  Somehow,  many  physicians  have  entertained  the 
erroneous  idea  that  the  radiation  from  infra-red  coils  penetrates  to  great 
depths.  Actually,  the  rays  from  the  far  portion  of  the  infra-red  spectrum, 
which  are  produced  by  these  nonluminous  or  "black  body"  radiators, 
penetrate  in  appreciable  amounts  to  a  depth  of  less  than  i  mm. 


Fig.  5.  An  ordinary  household  electrical  heater.  The  heating  unit  produces  radi- 
ation similar  to  that  emitted  by  the  therapeutic  infra-red  unit,  but  the  flatter  reflector 
tends  to  difi'use  the  radiation  (From  Krusen,  F.  H.:  Light  Therapy,  Ed.  2,  Hoeber,  New 
York,  1937). 

The  greatest  amount  of  penetration  of  convective  heat  can  be  ob- 
tained from  luminous  sources,  which  produce  considerable  amounts  of 
radiation  in  the  near  portion  of  the  infra-red  spectrum,  such  as  carbon 
filament  or  tungsten  filament  lamps  (Fig.  6a  and  b).  These  infra-red 
luminous  bulbs  can  be  placed  in  the  same  cup-shaped  reflectors  which 
are  employed  for  the  nonluminous  infra-red  coils.  The  penetration  through 
human  tissues  of  radiation  from  the  luminous  bulbs  has  been  estimated 
variously  up  to  depths  of  1.5  cm.  Recently,  however.  Hardy  and 
Muschenheim^"  reported  careful  investigations,  which  indicated  that  the 
transmission  through  skin  of  even  these  most  penetrating  infra-red  rays 

Vol.  I.  941 


METHODS  OF  APPLYING   HEAT  LOCALLY 


755 


Fig.  6.     Luminous  type  of  infra-red  unit  in  a  suitable  cup-shaped  reflector;     (a)  a 
tungsten  filament  lamp;    (b)  a  carbon  filament  lamp. 


Vol.  I.  941 


756 


PHYSICAL   MEDICINE 


is  slight.     They  found  that  about  95  per  cent,  of  the  rays  were  absorbed 
within  2  mm.  of  the  surface  and  99  per  cent,  within  3  mm. 

For  most  therapeutic  appUcations  it  will  be  advisable  to  employ  a 
source  of  radiation  which  is  rich  in  the  more  penetrating  near  infra-red 
rays.  Therefore,  convective  heat  treatments  usually  should  be  adminis- 
tered with  a  device  which  converges  the  rays  from  a  luminous  source  on 


\M 

„„i^f^m'jk    1 

i    ■: 

H 

Fig.  7.  A  radiant  heat  lamp,  luminous  type  of  infra-red  bulb,  with  a  special  black 
glass  filter,  which  eliminates  glare  but  does  transmit  most  of  the  more  penetrating  near 
infra-red  rays  (From  Krusen,  F.  H.:  A  new  type  of  filter  for  efficient  infra-red  radiation, 
Proc.  Staff  Meet.,  Mayo  Clin.,  1941,  XIV,  22). 

the  part  to  be  treated.  For  example,  one  type  of  luminous  therapeutic 
heat  bulb,  which  is  known  as  the  "Mazda  CX"  bulb,  is  particularly  rich 
in  the  slightly  more  penetrating  near  infra-red  rays.  Thirty  per  cent,  of 
the  radiation  from  this  type  of  bulb  is  within  the  most  penetrating  range 
with  wavelengths  between  770  and  1,200  millimicrons. 

One  disadvantage  of  the  high  voltage  heat  bulb  is  that  it  produces 
considerable  glare.  I  recently  have  described^^  a  new  type  of  infra-red 
lamp  with  a  special  black  glass  filter  which  transmits  most  of  the  penetrat- 

VoL.  I.  941 


METHODS  OF   APPLYING   HEAT   LOCALLY  757 

ing  near  infra-red  rays  but  cuts  off  practically  all  of  the  visible  rays  and 
thus  eliminates  glare  (Fig.  7).     This  lamp  si^ems  to  be  especially  valuable 


Fig.  8.  An  inexpensive  "clamp  lamp"  which  can  be  employed  at  home  for  pro- 
longed local  heating  of  various  regions  of  the  body  (From  Krusen,  F.  H.:  Physical  ther- 
apy in  arthritis,  with  special  reference  to  home  treatment,  Jour.  Am.  Med.  Assoc,  1940, 
CXV,  605). 

for  application  of  heat  to  the  face  and  to  the  upper  anterior  part  of  the 
body  because  the  patient  is  not  annoyed  by  glare. 

A  strange  phenomenon  has  been  the  development  in  this  country  of 
small  inexpensive  heat  lamps  consisting  of  a  bulb  on  a  small  reflector 
attached  to  a  handle.  It  is  undoubtedly  of  great  usefulness  to  have  in- 
expensive heat  lamps  readily  available,  but  the  catch  is  that  almost  no- 

VoL.  I.  941 


758 


PHYSICAL   MEDICINE 


body  wishes  to  hold  such  a  lamp  steadily  in  his  hand  long  enough  for  it 
to  produce  any  marked  therapeutic  effect.  It  usually  requires  at  least 
thirty  minutes  of  local  application  of  heat  to  produce  an  effective  in- 
crease in  temperature  of  the  tissues.  It  is  extremely  tiresome,  even  if  the 
hands  are  shifted,  to  hold  a  lamp  steadily  in  one  position  for  thirty  minutes. 


Fig.  9.  Institutional  type  of  baker.  This  is  a  luminous  heat  device  containing 
usually  four  to  twelve  light  bulbs. 

To  obviate  this  difficulty,  I  have  had  constructed  an  inexpensive 
"clamp  lamp"  which  was  described  a  few  years  ago^'.  This  lamp  has  a 
cup-shaped  reflector  containing  a  luminous  heat  bulb.  Instead  of  a  handle 
a  clamp  similar  to  that  employed  for  "photo-flash"  lamps  is  provided. 
This  inexpensive  clamp  lamp  can  be  attached  to  the  side  of  a  bed  or  to 
the  back  of  a  chair.  A  ball  and  socket  joint  permits  adjustment  of  the 
reflector  at  any  angle.  The  lamp  can  be  employed  easily  for  prolonged 
heating  of  various  local  regions  of  the  body  (Fig.  8). 

Vol.  I.  941 


PRINCIPLES   IN   APPLICATION   OF   HEAT 


759 


Still  extremely  serviceable  is  the  old  style  "baker"  which  consists  of 
a*  slightly  curved  rooflike  reflector  supported  by  adjustable  legs.  Beneath 
this  reflector  are  several  small  electric  light  bulbs.  This  tunnel-like 
heating  device  can  be  placed  over  a  leg,  an  arm  or  the  back  (Fig.  9).     A 


Fig.  10.     Inexpensive  homemade  baker.     Four  bulbs  are  covered   by  a  reflector  of 
sheet  tin  on  framework  of  iron  rods. 

similar,  less  elaborate  baker  for  home  use  can  be  constructed  of  four 
light  bulbs  covered  by  a  piece  of  polished  sheet  tin  supported  on  a  light 
framework  of  iron  rods  (Fig.   10). 


Physical  Principles  Concerned  in  the  Local  Application 

OF  Heat 

Since  heat  is  a  form  of  irregular  molecular  motion,  thermal  energy  can 
be  transmitted  from  one  body  to  another  by  continuation  of  this  molec- 
ular motion.  Interchanges  of  this  sort  are  taking  place  continually 
between  the  human  body  and  its  environment.  As  previously  mentioned, 
such  transmission  of  molecular  motion  can  take  place  by  conduction, 
convection  or  conversion. 

All  of  the  conductive  methods,  which  have  been  described,  require 
direct   application   of   the   hot   applicator   to   some   surface   of   the   body. 

Vol.  I.  941 


760 


PHYSICAL   MEDICINE 


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Action  and  Uses  of  Local  Heating 
Devices 

The  action  of  conductive  or  conversive  heat- 
ing is  superficial  because  the  penetration  of 
heat  is  always  sUght.  Normally  the  tempera- 
ture of  the  blood  in  various  peripheral  regions 
of  the  body  is  lower  than  the  central  tempera- 
ture of  approximately  98.6°  F.  (37°  C.)-  The 
temperature  of  the  skin,  fat  and  muscle  in 
peripheral  regions  varies  and  usually  is  con- 
siderably  lower   than    the    rectal    temperature. 

Vol.  I.  941 


I 


Luminous  and  infra-red  rays  result  from  electromagnetic  disturbances  of 
the  ether.  According  to  Huygen's  wave  theory  there  is  a  propagation  of 
energy  in  the  form  of  waves.  Wavelength  is  the  distance  between  the 
crests  of  adjoining  ether  waves. 

Because  the  frequency  of  vibration  of  a 
given  source  of  heat  energy  is  uniform,  and  the 
velocity  of  the  radiation  is  constant,  the  dis- 
tance between  any  two  adjacent  waves  will  be 
identical  with  the  distance  between  any  other 
two  waves  derived  from  the  same  source. 

The  electromagnetic  spectrum  can  be  defined 
as  a  graphic  representation  of  the  various  waves 
of  energy  in  ascending  order  of  length  (Fig.  ii). 
Starting  with  the  shortest  known  rays,  the  cos- 
mic rays,  it  will  be  seen  that  the  next  short- 
est in  ascending  order  are  the  gamma  rays  of 
radium.  Forming  a  continuous  spectrum  in 
succession  of  increasing  wavelengths  from  these 
are  the  roentgen  rays,  ultraviolet  rays,  visible 
light,  infra-red  rays,  hertzian  waves  including 
the  short  and  long  radio  waves  and  alternat- 
ing current  waves. 

Those  portions  of  the  spectrum  which  con- 
tain radiations  employed  for  convective  heating 
are  the  visible  and  infra-red  regions.  The  wave- 
lengths of  the  rays  from  this  portion  of  the 
spectrum  vary  between  290  and  15,000  milli- 
microns. 


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ACTION   AND   USES   OF   HEAT   DEVICES  761 

Local  applications  of  heat  will  tend  to  raise  the  temperature  in  periph- 
eral regions. 

It  is  probable  that  bodily  tissues  cannot  tolerate  a  prolonged  increase 
of  external  temperature  to  more  than  113°  F.  (45°  C.)  without  being 
damaged.  For  short  periods  of  time  they  can  tolerate  changes  of  external 
temperature  exceeding  36°  F.  (20°  C.)  without  evidence  of  injury.  Local 
application  of  heat  produces  dilatation  of  blood  vessels  and  an  increase  in 
the  rate  of  fllow  of  the  blood.  The  tendency  toward  rapid  dissemination 
of  the  heat  finally  may  result  in  an  increase  in  the  systemic  temperature. 
There  is  evidence  that  the  heat  causes  increase  of  phagocytic  and  local 
metabolic  activity.  Heating  of  the  blood  increases  carbon  dioxide  tension 
and  acidity.  It  has  been  suggested'^  that  these  changes  may  be  of  some 
value  in  modifying  the  reactions  of  tissues  to  infection. 

A  point  worth  keeping  in  mind  is  that  local  exposure  to  infra-red  ra- 
diation will  produce  a  rise  of  temperature  of  a  considerable  volume  of 
blood  as  it  circulates  through  the  cutaneous  capillaries.  The  temperature 
of  the  blood  will  reach  a  level  exceeding  that  of  the  average  systemic  fever 
without  any  appreciable  rise  in  the  systemic  temperature.  Local  applica- 
tions of  heat  possibly  may  stimulate  intracellular  oxidation.  Likewise 
sweating  and  muscular  relaxation  are  produced  by  local  heating. 

Daily  treatments  for  thirty  minutes  in  the  hot  air  chambers  and 
blowers  have  been  recommended  particularly  as  an  adjunct  in  the  manage- 
ment of  various  forms  of  arthritis.  The  vaginal  applicator,  which  is 
heated  by  circulating  hot  air,  usually  is  employed  for  sessions  of  one  hour 
daily  in  treatment  for  specific  and  nonspecific  inflammatory  disease  of  the 
pelvis. 

Like  the  hot  air  device,  the  Elliott  apparatus,  which  circulates  hot 
water  through  a  distensible  rubber  bag  within  the  vagina,  is  employed 
chiefly  for  pelvic  inflammatory  disease.  The  water  pressure  meter  should 
register  2  or  3  pounds  (0.9  or  1.4  kg.).  Hourly  treatments  usually  are 
given  once  or  twice  a  day.  Randall  and  P*  found  that  complete  clinical 
remissions  were  obtained  in  55  per  cent,  of  our  45  cases  of  chronic  gonor- 
rheal inflammatory  disease  of  the  pelvis  in  which  treatment  with  the 
Elliott  device  was  employed;  in  an  additional  22  per  cent,  negative  cul- 
tures developed,  but  there  was  evidence  of  residual  salpingo-oophoritis; 
in  II  per  cent,  improvement  did  not  occur,  and  in  11  per  cent,  insufficient 
treatment  was  received.  Of  our  group  of  173  patients  suffering  from 
nonspecific  pelvic  inflammatory  disease  30  per  cent,  were  greatly  improved 
after  Elliott  treatment;  27.7  per  cent,  were  moderately  improved;  9.8  per 
cent,  were  slightly  improved,  and  5.7  per  cent,  were  unimproved.  Surgical 
treatment  was  required  in  26.5  per  cent,  of  the  cases.     Pelvic  heating  with 

Vol.  I.  941 


762  PHYSICAL   MEDICINE 

the  Elliott  device  was  employed  successfully  to  promote  absorption  of 
exudates  following  pelvic  operation. 

The  Elliott  treatment  has  been  applied  through  a  rectal  applicator 
for  chronic  prostatitis,  specific  and  nonspecific,  and  a  urethral  applicator 
was  employed  by  Emmett  in  treatment  for  nonspecific  urethritis  among 
females.  Welch  and  I  have  administered  Elliott  treatments  through  a 
colonic  stoma  to  lessen  edema  of  the  spur  and  to  permit  earlier  application 
of  clamps  for  the  second  stage  of  the  Mikulicz  operation. 

The  chemical  heating  pads  have  been  employed  chiefly  for  chronic 
inflammation  of  the  eye  or  nasal  accessory  sinuses.  The  larger  chemical 
heating  pad  has  been  used  as  a  substitute  for  the  hot  water  bottle  and 
has  the  advantage  that  it  will  remain  hot  for  a  longer  period. 

Ordinary  electrical  heating  pads  should  not  be  used  unless  more  suit- 
able methods  of  heating  are  not  available.  The  compress  with  accurate 
thermostatic  control  can  be  employed  to  maintain  the  warmth  of  wet 
dressings  at  proper  level  for  infections,  acute  inflammations,  cutaneous 
diseases  and  surgical  conditions.  The  electrically  heated  sleeves,  cufi^s 
and  pads,  which  have  accurate  control,  can  be  employed  for  peripheral 
vascular  diseases,  arthritis  and  traumatic  lesions. 

Applications  of  hot  paraffin  have  been  recommended  chiefly  for  con- 
tractures,  arthritis,   fibrositis,   post-traumatic  stiff  joints  and  lacerations. 

The  application  of  infra-red  radiation  has  been  advocated  for  numerous 
conditions.  It  tends  to  promote  absorption  of  exudates  because  heat 
produces  not  a  passive  congestion  but  an  active  hyperemia  with  an  in- 
crease in  the  volume  of  blood  flowing  through  the  region  rather  than 
engorgement  and  stagnation. 

Local  treatment  with  infra-red  radiation  has  been  recommended^^-  ^* 
for  various  types  of  neuritis,  myositis,  fibrositis  and  arthritis,  for  circula- 
tory diseases,  for  certain  types  of  paralysis  and  also  for  traumatic  lesions 
such  as  sprains,  contusions,  dislocations  and  fractures.  It  always  should 
be  remembered  that  various  conductive  methods  of  applying  heat  often 
can  be  substituted  for  infra-red  radiation  or  vice  versa.  The  therapeutic 
efi^ects  are  essentially  the  same.  The  choice  of  the  superficial  heating  agent 
will  be  largely  a  matter  of  convenience. 

Following  trauma  heat  should  not  be  applied  until  the  danger  of  cap- 
illary oozing  with  extravasation  and  ecchymosis  has  ceased.  This  usually 
will  require  twenty-four  to  forty-eight  hours.  During  this  time  tight 
dressings,  immobilization  and  applications  of  cold  are  in  order.  As  soon 
as  this  danger  disappears,  applications  of  heat  for  periods  of  thirty  min- 
utes or  longer,  once  or  twice  a  day,  should  be  begun.  After  the  applica- 
tions of  heat,   massage  sometimes  can   be  administered.     The  heat  and 

Vol.  I.  941 


CONTRAINDICATIONS  TO   HEAT  APPLICATIONS        763 

massage  will  tend  to  promote  absorption  and  to  prevent  the  formation  of 
organized  hematomas. 

Traumatic  synovitis,  tenosynovitis,  bursitis,  spastic  muscles  and 
strained  muscles  often  can  be  benefited  by  local  applications  of  conductive 
or  convective  heat. 

Contraindications  to  the  Local  Application  of  Heat 

The  great  danger  in  applying  any  form  of  therapeutic  heating  is  that 
burns  may  be  caused.  Patients  have  been  known  to  permit  themselves 
to  be  burned  thinking  that  they  were  supposed  to  tolerate  the  pain.  It  is 
not  sufficient  to  give  the  patient  a  bell  and  to  tell  him  to  ring  it  if  the 
part  becomes  too  hot.  I  recall  one  patient  who,  although  he  had  been  so 
instructed,  promptly  permitted  himself  to  be  burned  and  then  explained 
that  he  did  not  know  how  much  "too  hot"  was.  Therefore,  the  patient 
must  be  told  that  he  should  feel  only  comfortable  warmth;  that  the 
minute  he  feels  the  slightest  discomfort,  he  should  ring.  He  should  be 
warned  that  excessive  heat  will  do  more  harm  than  good. 

Heat  always  must  be  applied  with  extreme  caution  to  extremities  in 
which  the  circulation  is  impaired.  In  the  presence  of  peripheral  vascular 
disease  heat  will  be  disseminated  poorly  by  the  impaired  circulation; 
therefore,  burns  are  more  likely  to  occur.  Furthermore,  if  a  burn  does 
result,  slowly  healing  lesions  or  even  gangrene  may  occur  in  the  devita- 
lized tissue.  It  should  be  remembered  in  dealing  with  peripheral  vascular 
diseases  that  the  local  application  of  heat  to  an  unaffected  region  may 
produce  vasodilatation  in  the  affected  part.  Local  heating  of  an  unin- 
volved  region  may  be  just  as  effective  as  direct  heating,  and  it  is  much 
safer.  If  heat  is  to  be  applied  locally  to  the  affected  extremity,  prolonged 
applications  at  fairly  low  temperatures,  91.4°  to  95°  F.  (33°  to  35°  C), 
are  safer  than  short  exposures  at  high  temperature. 

Heat  always  must  be  applied  with  great  caution  over  old  scars 
which  are  comparatively  avascular  and  will  blister  readily.  It  often  is 
wise  to  cover  small  scars  in  a  region  which  is  to  be  heated.  Likewise 
heat  must  be  applied  with  extreme  caution  over  anesthetic  regions. 
Because  there  is  no  sensation,  the  patient  may  be  burned  without  realiz- 
ing it. 

Knappi^  recently  has  expressed  the  opinion  that  in  most  instances 
just  sufficient  heat  should  be  applied  to  produce  a  faint  pink  blush  on  the 
skin.  He  concluded  that,  if  there  was  a  mottled  erythema  of  the  skin, 
the  heat  was  too  intense.  It  seems  obvious  that  the  mottling,  so  com- 
monly observed   during  intense  heating  of   the   skin,   indicates  unequal 

Vol.  I.  941 


764  PHYSICAL   MEDICINE 

distribution  of  the  hyperemia  in  the  region  under  treatment.  Certainly 
it  is  safer  to  avoid  the  mottUng  when  possible. 

Local  exposures  to  heat  may  aggravate  certain  cutaneous  rashes.  As  a 
rule,  local  heat  should  not  be  applied  in  febrile  conditions.  Occasionally 
sensitivity  to  heat,  attributable  usually  to  derangement  of  the  heat  regu- 
lating mechanism,  may  be  encountered.  In  such  instances  local  heating 
must  be  applied  with  great  caution. 

When  Elliott  treatments  are  administered  to  the  vagina,  incorrect 
placing  or  improper  distention  of  the  applicator  may  produce  excessive 
localization  of  heat  in  a  small  region,  and  severe  burns  may  ensue.  Large 
sloughs  of  the  anterior  vaginal  wall  have  been  reported  after  incorrect 
employment  of  the  procedure. 

If  hot  paraffin  is  used  for  local  heating,  in  rare  instances  a  mild  paraffin 
rash  may  be  produced. 

Summary  of  Data  on  Local  Heat 

There  are  numerous,  readily  available  sources  of  heat  which  can  be 
employed  in  local  treatment  for  various  diseases.  Devices  heated  by 
warm  air,  warm  water,  chemicals,  electrical  coils,  previously  heated  solids 
and  semisolids  and  several  sources  of  infra-red  radiation  can  be  used. 

These  devices  are  employed  chiefly  to  increase  local  temperature  and 
circulation,  to  increase  local  metabolism,  to  promote  absorption  and  to 
relieve  muscular  spasm.  Local  applications  of  heat  are  indicated  es- 
pecially in  the  management  of  acute  and  chronic  inflammations,  impair- 
ment of  circulation  and  various  traumatic  lesions.  Heat  should  be  applied 
with  great  caution  in  the  presence  of  peripheral  vascular  disease,  scars  or 
anesthesia  of  the  skin. 

BIBLIOGRAPHY   OF   LOCAL   HEAT   APPLICATIONS 

1.  BIER,  AUGUST:    Hyperemia  as  a  Therapeutic  Agent,  (translated  by  G.  M. 

Blech),  Frank  S.  Betz  Co.,  Hammond,   Indiana,   1913. 

2.  MEYER,  \V.  and  SCHAHEDEN,  V.:    Bier's  Hyperemic  Treatment  in  Surgery, 

Medicine   and    the   Specialities;    a    Manual    of   its    Practical   Application, 
Saunders,  Philadelphia,  1908. 

3.  NEWMAN,  L.   B.:    An  improved  method  for  applying  pelvic  heat  using  air. 

Am.  Jour.  Obst.  and  Gynec,  1939,  XXXVHI,  725. 

4.  COUNCIL  ON  PHYSICAL  THERAPY:    Altherm  eye  pad  acceptable,  Jour. 

Am.  Med.  Assoc,  1934,  CHI,  563. 

5.  COUNCIL  ON  PHYSICAL  THERAPY:   Altherm  sinus  pad  acceptable.  Jour. 

Am.  Med.  Assoc,  1936,  CVI,  921. 
Vol.  I.  941 


BIBLIOGRAPHY  765 

6.  COUNCIL  ON   PHYSICAL  THERAPY:    Thermal  self-heating  heat  pad  ac- 

ceptable, Jour.  Am.  Med.  Assoc,   1935,  CV,   118. 

7.  COUNCIL  ON   PHYSICAL  THERAPY:    Cooley  compress  acceptable,  Jour. 

Am.  Med.  Assoc,  1939,  CXIII,  1139. 

8.  BROWN,   G.   E.,   Jr.   and  ALLEN,    E.   V.:    Personal    communication   to  the 

author. 

9.  KRUSEN,  F.  H.:    Physical  Medicine,  Saunders,  Philadelphia,  1941. 

10.  HARDY,   J.    D.   and    MUSCHENHEIM,    C:     Radiation    of    heat    from    the 

human    body.      V.   The   transmission   of   infra-red   radiation    through  skin, 
Jour.  Clin.  Invest.,   1936,  XV,   i. 

11.  KRUSEN,  F.  H.:    A  new  type  of  filter  for  efficient  infra-red  radiation,  Proc 

Staff  Meet.,  Mayo  Clin.,   1941,  XVI,  22. 

12.  KRUSEN,  F.  H.:    A  simple  inexpensive   heat   lamp,   Jour.  Am.   Med.   Assoc, 

1936,  CVII,  780. 

13.  BAZETT,  H.  C:    The  physiological  basis   for  the  use  of  heat.     In  Principles 

and   Practice  of  Physical  Therapy,  Vol.   I,   pp.    1-29,   Prior,   Hagerstovvn, 
Maryland,  1934. 

14.  RANDALL,  L.  M.  and  KRUSEN,  F.  H.:   A  consideration  of  the  Elliott  treat- 

ment of  pelvic  inflammatory  disease  of  women,  Arch.  Phys.  Therapy,  1937, 
XVIII,  283. 

15.  TROUP,  W.  A.:    Therapeutic  Uses  of  Infra-red  Rays,  Actinic  Press,  London, 

1930. 

16.  TROUP,  W.  A.:    Infra-red  and  U-V  irradiation  of  injuries  in  sport,  Brit.  Jour. 

Phys.  Med.,  1935,  IX,  172. 

17.  KNAPP,  M.  E.:    Personal  communication  to  the  author. 

Sept.  I,  1941. 


Vol.  I.  941 


766  PHYSICAL   MEDICINE 

GENERAL  APPLICATION   OF   HEAT 

The  general  or  systemic  heating  of  the  human  body  for  therapeutic 
purposes  now  is  spoken  of  commonly  as  "fever  therapy".  There  are 
several  methods  of  obtaining  increases  in  bodily  temperature  by  physical 
means,  and  recently  much  interest  has  developed  in  the  employment  of 
these  devices  for  the  production  of  artificial  fevers. 

A  few  decades  ago  fever  was  considered  by  physicians  to  be  a  mani- 
festation of  disease  which  should  be  combated.  Therefore,  much  of  the 
internal  medication,  chiefly  with  the  derivatives  of  coal  tar,  was  directed 
toward  abolishing  fevers.  At  present  it  is  believed  that  spontaneous 
fever  often  is  an  indication  of  the  benign  efforts  of  nature  to  overcome 
disease.  Today  in  certain  types  of  disease,  in  which  spontaneous  fever 
does  not  occur,  the  physician  makes  a  therapeutic  efTort  to  produce  a 
fever  by  physical  or  other  means. 

Recently  much  fundamental  and  clinical  research  has  been  done  in 
this  field.  Fever  therapy,  at  least  when  high  temperatures  are  used,  now 
is  considered  a  major  procedure,  which  should  be  employed  only  in  well- 
equipped  institutions  possessing  skilled  personnel.  The  procedure  seems 
logical  and  appears  to  have  far-reaching  possibilities. 

Methods  of  Producing  General  Heating  of  the  Body 
(Fever  Therapy) 

Rises  in  systemic  temperature  can  be  produced  physically  by  the  use 
of  (i)  cabinets  within  which  circulates  hot  humid  air,  (2)  cabinets  heated 
by  luminous  heat  bulbs  or  nonluminous  heating  coils,  (3)  diathermy, 
(4)  hot  tub  or  spray  baths  or  (5)  conductive  heating  by  means  of  heated 
blankets  or  sleeping  bags. 

Hot  Humid  Air  Cabinets.  —  The  device  for  inducing  fever  by  physical 
means  which  is  employed  most  commonly  in  this  country  is  the  hot 
humid  air  cabinet.  A  plan  of  one  of  the  earlier  models,  known  as  the 
Kettering  hypertherm,  is  illustrated  in  Fig.  12.  One  of  the  newer  models 
of  the  "hypertherm"  is  illustrated  in  Fig.  13a  and  b.  This  type  of 
apparatus  was  developed  by  Simpson  and  KendelP-  -  at  the  Kettering 
Institute  for  Medical  Research  in  Dayton,  Ohio.  I  have  employed  it 
extensively  and  have  found  it  satisfactory  for  the  production  and  main- 
tenance of  prolonged  high  fevers. 

Warm  humid  air  is  circulated  slowly  through  the  cabinet.  The  air 
temperature  varies  between  110°  and  130°  F.  (43.3°  and  54.4°  C),  and  the 
humidity  usually  is  kept  above  80  per  cent.     Temperature  and  humidity 

Vol.  I.  941 


METHODS  OF   GENERAL   HEATING 


767 


Vol.  I.  941 


768 


PHYSICAL   MEDICINE 


Fig.  13.  A  metal  fever  cabinet  known  as  the  hypertherm,  which  has  been  developed 
on  the  same  principles  as  the  original  Kettering  hypertherm;  (a)  cabinet  closed;  (b)  cabi- 
net open. 

are  modified  readily,  as  desired,  so  that  the  procedure  is  excellent,  be- 
cause it  permits  such  accurate  control  of  bodily  temperature. 
Vol.  I.  941 


METHODS   OF   GENERAL   HEATING 


769 


Cabinets  Heated  by  Luminous  Bulbs  or  Nonluminous  Ileal  Coils. — A 
fever  cabinet  heated  by  luminous  bulbs  can  be  constructed  for  about 
Si50^  Another  one  has  been  described^  which  can  be  built  for  consider- 
ably less  than  Sioo.  The  plan  of  such  a  cabinet,  which  was  developed  by 
Sheard,  is  illustrated  in  Fig.   14.     Sheard's  cabinet  differs  from  the  other 


Fig.   14.      Plan   of  the   Sheard  luminous  heat   fever  cabinet    (From   Krusen,   F. 
Physical   Medicine,   Philadelphia,   Saunders,    1941). 

luminous  heat  cabinets  in  having  a  humidifying  mechanism  attached  and 
in  being  more  heavily  insulated.  The  other  luminous  cabinets  mentioned 
depend  on  moisture  from  the  perspiration  of  the  patient  to  humidify  the 
still  air  of  the  cabinet.  This  latter  plan  is  feasible  because,  if  the  cabinet 
is  kept  closed,  the  air  soon  becomes  saturated  with  moisture  as  the 
patient's  temperature  rises  and  he  begins  to  perspire. 

Various  types  of  fever  cabinets,  which  have  been  heated  by  nonlu- 
minous heating  elements,  have  been  marketed  also.  This  type  of  cabinet 
has  not  been  employed  so  extensively  as  have  other  kinds  of  fever  pro- 
ducing machines. 

Diathermy.  —  A  method  of  heating  the  entire  body  by  means  of  con- 
ventional diathermy  formerly  was  employed  for  the  production  of  arti- 
ficial fevers,  but  this  procedure  now  has  become  obsolete.  At  present  the 
newer  short  wave  diathermy  machines  frequently  are  used  for  induction  of 

Vol.  I.  941 


770 


PHYSICAL   MEDICINE 


artificial  fevers.  A  common  procedure  is  to  introduce  a  long  induction  cable 
from  a  short-wave  diathermy  machine  into  one  of  the  humid  air  cabinets 
(Fig.  15).  The  diathermy  is  used  to  induce  the  fever  which  then  is  main- 
tained by  means  of  the  insulated  cabinet.  I  have  obtained  equally  satis- 
factory results  by  induction  of  fever  with  the  hot  humid  air  alone  and 
prefer  this  simpler  method,  although  there  is  no  great  objection  to  induc- 
ing the  fever  with  diathermy. 

Halphen  and  Auclair^  employed  a  powerful  short-wave  diathermy  ma- 


FlG.  15.  A  fever  cabinet  into  which  extends  a  short  wave  diathermy  induction  coil. 
Diathermy  is  employed  to  induce  the  fever  which  is  maintained  by  the  insulated  cabinet 
(From  Krusen,  F.  H.:    Physical  Medicine,  Philadelphia,  Saunders,  1941). 

chine  and  a  nonmetallic  treatment  bed.  The  patient,  dressed  in  a  bath- 
robe, lay  on  the  bed  and  was  covered  with  blankets.  Two  large  flat 
diathermy  electrodes  were  placed  on  the  same  plane  beneath  the  bed  at  a 
distance  of  approximately  10  cm.  from  the  patient's  back.  The  patient's 
body  thus  was  within  the  high  frequency  electrical  field  adjacent  to  the 
electrodes,  conversive  heat  within  his  body  caused  his  systemic  tempera- 
ture to  rise,  and  loss  of  heat  was  prevented  by  the  blankets.  The  great 
objection  to  the  use  of  blankets  for  insulation  is  that  as  the  temperature 
rises,  the  patient  becomes  uncomfortable  under  the  heavy  coverings. 
Vol.  I.  941 


PHYSICAL   PRINCIPLES    IN   GENERAL    HEATING         771 

Hot  Tub  or  Spray  Baths.  —  Tub  baths  can  be  employed  to  advantage 
for  the  induction  of  short  low  fevers.  Prolonged  hot  tub  baths  are  de- 
pressing and  may  be  dangerous.  Deaths  from  prolonged  hot  baths  have 
been  reported.  I  frequently  employ  the  short  hot  baths  for  therapeutic 
effects,  but  these  baths  never  are  permitted  to  last  more  than  an  hour  and 
usually  do  not  last  more  than  thirty  minutes. 

The  method  consists  of  immersing  the  patient  to  the  neck  in  water 
which  is  at  a  temperature  of  105°  to  iio°F.  (40.5°  to  43.5°  C).  He  re- 
mains in  the  tub  until  his  systemic  temperature  is  within  1.5°  F.  (0.83°  C.) 
of  the  desired  level.  Then  the  water  is  cooled  to  the  temperature  of  the 
patient,  or  he  is  removed  from  the  tub  and  placed  in  a  blanket,  sleeping 
bag  or  insulated  cabinet.  Usually  his  temperature  will  continue  to  rise 
until  it  reaches  the  desired  level  and  will  tend  to  remain  there  as  long  as 
he  remains  covered.  The  method  is  comparatively  safe  and  simple,  if  it 
is  not  desired  to  increase  the  systemic  temperature  to  more  than  103°  to 
104°  F.  (39.4°  to40°C.). 

Hot  spray  cabinets  have  been  manufactured,  which  resemble  somewhat 
the  other  types  of  fever  cabinets.  The  patient's  head  protrudes  from  one 
end  of  the  cabinet,  and  his  nude  body  is  sprayed  with  a  mist  of  nebulized 
hot  water.  This  form  of  fever  apparatus  has  been  used  successfully  in 
some  institutions. 

Conductive  Heating.  —  Electrical  blankets,  hot  water  bottles  and 
blankets,  and  fever  bags,  all,  have  been  employed  to  heat  and  to  insulate 
the  body  of  the  patient  in  order  to  produce  artificial  fever.  Unless  some 
means  of  keeping  the  heavy  coverings  off  the  patient's  body  is  employed, 
all  such  methods  are  extremely  uncomfortable.  Like  hot  baths  they  should 
not  be  used  to  raise  the  svstemic  temperature  to  more  than  103°  to  104°  F. 
(39.4°  to  40°  C). 

Physical  Principles  Concerned  in  the  General 
Application  of  Heat 

The  production  of  artificial  fevers  by  physical  means  depends  on  two 
factors;  increased  input  and  decreased  output  of  heat  energy.  Practically 
all  of  the  methods  for  physical  induction  of  fever  employ  both  factors. 
Some  method  of  increasing  temperature  is  used  in  conjunction  with  some 
method  of  insulating  the  body  to  limit  loss  of  heat.  The  input  of  heat 
generally  is  achieved  by  increasing  the  environmental  temperature  of  the 
patient  or  by  the  application  of  high  frequency  currents,  and  the  egress  of 
heat  usually  is  lessened  by  placing  the  patient  in  an  insulating  medium 
of  some  sort. 

Vol.  I.  941 


772  PHYSICAL   MEDICINE 

From  a  physical  standpoint  the  regulation  or  prevention  of  loss  of 
heat  is  more  important  than  the  application  of  heat  in  producing  artifi- 
cial fevers.  This  is  owing  to  the  fact  that  the  heat  eliminating  mechanism 
of  human  beings,  when  performing  in  a  normal  manner,  can  rid  the  body 
of  an  excess  of  heat  at  a  rate  which  is  twelve  times  as  great  as  the  basal 
rate  of  heat  production. 

Action  and  Uses  of  Devices  for  the  General  Application 
OF  Heat  (Fever  Therapy) 

High  physically  induced  fevers  increase  the  pulse  and  circulatory  rates. 
The  velocity  of  the  blood  may  be  increased  as  much  as  400  per  cent. 
During  induction  of  fever  the  cardiac  filling  time  is  shortened  temporarily 
so  that  partial  decompensation  may  occur.  When  fever  therapy  is  accom- 
panied by  profuse  sweating,  the  reduction  in  blood  plasma  may  be  so 
great  that  peripheral  vascular  collapse  ensues.  During  fever  therapy  the 
visible  capillaries  of  the  nail  beds  are  increased  in  size  and  number. 
Physically  induced  fevers  produce  leukocytosis.  An  initial  decrease  in 
the  number  of  leukocytes  is  followed  immediately  by  a  tidelike  increase; 
the  new  cells  are  added  in  waves  for  several  hours  after  completion  of  the 
febrile  session.  The  number  of  leukocytes  then  gradually  diminishes  and 
attains  prefebrile  levels  in  about  twenty-four  hours.  Leukocytosis  is 
greater  several  hours  after  the  end  of  the  fever  session  than  at  its  close. 
At  the  peak  there  may  be  more  than  40,000  leukocytes  per  cubic  milli- 
meter of  blood.  There  is  a  relative  increase  in  neutrophils  and  a  relative 
decrease  in  lymphocytes  following  fever  therapy.  Excessive  perspiration 
accompanying  fever  therapy  may  cause  a  marked  decrease  in  the  chlo- 
rides of  the  blood  serum. 

At  the  beginning  of  a  session  of  fever  the  content  of  oxygen  and  the 
oxygen  combining  power  of  the  venous  blood  are  increased.  Despite  this 
increase  of  oxygen,  the  increased  metabolic  activity  and  the  increased 
demand  for  oxygen  in  the  tissues  may  result  finally  in  anoxia  of  the  tis- 
sues, particularly  if  the  circulation  begins  to  fail  because  of  circulatory 
collapse.  The  danger  of  anoxia  and  likewise  the  danger  of  circulatory 
collapse  owing  to  loss  of  bodily  fluids  from  excessive  perspiration  always 
are  present  during  prolonged  sessions  of  artificial  fever. 

The  growth  of  certain  organisms  is  destroyed  or  attenuated  at  tem- 
peratures induced  by  artificial  fever.  The  Neisseria  gonorrJicex  generally 
is  destroyed  at  a  temperature  of  106°  to  107°  F.  (41.1°  to  41.6°  C.)  in  6 
to  34  hours,  the  mean  number  of  hours  being  16.1.  The  thermal  death 
time  of  the  Treponema  pallidum  at  102.2°  F.  (39.0°  C.)  is  five  hours  and 

Vol.  L  941 


ACTION  AND   USES  OF   FEVER  THERAPY  773 

at  106.8°  F.  (41.5°  C.)  is  one  hour.  Nearly  all  strains  of  meningococci 
are  attenuated  greatly  or  destroyed  at  temperatures  of  104°  to  107.6°  F. 
(40°  to  42°  C.)  applied  for  five  hours. 

Arthritis.  —  Fever  therapy  has  been  employed  in  treatment  for  acute 
and  chronic  atrophic  arthritis.  It  seems  of  benefit  in  a  certain  percentage 
of  the  acute  cases.  Short  sessions  of  thirty  minutes,  given  every  day  or 
so,  seem  to  assist  in  controlling  exacerbations  of  chronic  atrophic  arthritis. 

Bronchial  Asthma.  —  For  bronchial  asthma,  which  has  failed  to  re- 
spond to  the  usual  therapeutic  procedures,  fever  therapy  has  been  used. 
Although  this  treatment  has  not  been  too  successful,  nevertheless  in  some 
instances  it  has  caused  remission  of  symptoms  for  a  year.  Usually  the 
remission,  if  it  occurs  at  all,  lasts  only  for  a  few  weeks. 

Sydenham's  Chorea.  —  Fever  therapy  now  is  considered  by  some 
authorities"  "the  method  of  choice  in  chorea".  Of  76  collected  cases  of 
Sydenham's  chorea  in  which  fever  treatment  was  given,  I  found  that  in 
more  than  72  per  cent,  recovery  occurred,  and  in  an  additional  21  per 
cent,  marked  improvement  was  noted.  Neymann's^  previous  analysis  of 
69  cases  indicated  recovery  in  77  per  cent,  and  improvement  in  17  per  cent. 

Endocarditis  Lenta.  —  The  use  of  fever  therapy  in  treatment  for  endo- 
carditis lenta,  subacute  bacterial  endocarditis,  is  particularly  interesting. 
In  1933  Bierman^  employed  fever  therapy  without  additional  chemother- 
apy for  subacute  bacterial  endocarditis.  He  reported  that  in  this  case 
"showers  of  numerous  emboli  caused  an  exitus".  In  1936  P  reported 
that  I  had  tried  artificial  fever  therapy  in  endocarditis  lenta  and  had 
abandoned  it  because  of  the  apparently  increased  danger  of  embolism. 
In  1937  Dry  and  Willius'°  treated  four  patients,  who  had  subacute  bac- 
terial endocarditis,  with  fever  therapy  and  came  to  the  conclusion  that, 
despite  the  fact  that  fever  therapy  enhanced  cellular  reactions  and  bodily 
defense  processes,  Streptococcus  viridans  seemed  to  be  able  to  resist  the 
highest  temperatures  which  were  humanly  tolerable. 

In  1941  Bierman  and  Baehr^'  reported  two  cases  of  subacute  bacterial 
endocarditis  in  which  treatment  with  a  combination  of  sulfanilamide  and 
fever  proved  successful.  Their  first  patient  was  treated  in  1938.  In  1940 
Bennett  and  P'-,  following  up  Baehr  and  Bierman's  successful  1938  case, 
reported  six  cases  of  subacute  bacterial  endocarditis  in  which  treatment 
with  combined  fever  and  sulfanilamide  was  unsuccessful.  The  combined 
therapy  in  our  opinion  appeared  to  have  a  definite  though  transient  in- 
fluence on  the  disease,  for,  despite  the  ultimate  failure,  culture  of  the 
blood  following  treatment  revealed  either  a  definite  decrease  in  the  num- 
ber or  a  temporary  complete  disappearance,  of  bacterial  colonies. 

In  1 94 1  Lichtman  and  Bierman^  reported  that  of  200  cases  of  subacute 

Vol.  I.  941 


774  PHYSICAL   MEDICINE 

bacterial  endocarditis  caused  by  nonhemolytic  Streptococcus  viridans,  in 
which  the  sulfonamide  drugs  were  administered,  recovery  occurred  in  12 
(6  per  cent.).  Recovery  occurred  in  5  (11.6  per  cent.)  of  43  cases  in  which 
combined  chemotherapy  and  heparin  were  used  and  in  9  (20  per  cent.)  of 
45  cases  in  which  combined  chemotherapy  and  fever  therapy  (either 
physically  induced  or  induced  by  typhoid-paratyphoid  vaccine)  were  em- 
ployed. They  concluded:  "The  combined  methods  of  therapy  seem  to 
promise  a  greater  incidence  of  recovery  than  may  be  anticipated  in  the 
natural  course  of  the  disease  or  after  treatment  with  sulfonamide  drugs 
alone." 

The  series  of  cases  reported  to  date  is  too  small  to  have  any  great 
statistical  significance;  it  is  possible  that  the  6  failures,  reported  by 
Bennett  and  myself,  happened  to  be  drawn  from  the  large  group  of  pa- 
tients who  failed  to  respond.  In  the  light  of  present  evidence,  therefore, 
it  seems  logical  to  consider  the  use  of  combined  fever  and  chemotherapy 
in  this  nearly  hopeless  group  of  cases.  Additional  experience  may  modify 
this  opinion.  At  present  there  seems  to  be  nothing  better  to  offer. 
Bierman  and  Baehr"  concluded  that  their  experience  indicated  "that 
physically  induced  pyrexia  enhances  the  value  of  chemotherapy  in  the 
treatment  of  subacute  bacterial  endocarditis".  Their  clinical  results 
supported  "the  in  vitro  observations  of  White'^  that  the  effectiveness  of 
the  sulfonamide  drugs  is  materially  enhanced  at  sustained  higher  eleva- 
tions of  temperature". 

Gonorrhea.  —  I  have  been  interested  especially  in  the  treatment  of 
gonorrhea  by  means  of  fever  therapy  and  more  recently  in  treatment  by 
means  of  a  combination  of  fever  therapy  and  the  sulfonamide  drugs  for 
gonorrhea  which  is  resistant  to  chemotherapy  alone.  In  a  series  of  415 
cases  of  proved  gonorrhea  in  which  adequate  fever  therapy  was  adminis- 
tered, after  an  average  of  four  fever  sessions  per  patient,  Randall,  Stuhler 
and  I  found  that  there  were  apparent,  complete,  clinical  remissions  in 
94.1  per  cent".  Follow-up  studies  revealed  that  the  disease  recurred  in 
not  more  than  3  to  5  per  cent.^^.  Of  1,157  collected  cases  of  acute  and 
chronic  gonorrhea  treated  by  artificial  fever  V^  found  that  apparent  cures 
were  reported  in  87.4  per  cent,  and  failures  in  12.6  per  cent. 

Despite  these  excellent  results  with  fever  therapy  alone  with  the  ad- 
vent of  the  sulfonamide  drugs  it  became  apparent  that  they  would  have  a 
curative  effect  in  a  high  percentage  of  cases  of  gonorrhea.  The  adminis- 
tration of  these  drugs  under  proper  control  is  certainly  a  much  less  rigor- 
ous procedure  than  is  fever  therapy.  Therefore,  it  is  recommended  at 
present  that  chemotherapy  be  tried  first  before  fever  therapy  is  ad- 
ministered for  gonorrhea. 

Vol.  I.  941 


ACTION   AND   USES   OF   FEVER  THERAPY  775 

Chemotherapy  has  failed  to  cure  gonorrhea  in  32  per  cent,  of  the  cases 
reported  by  Dees  and  Young'^  in  their  recent  review  of  the  Hterature.  It 
is  in  this  group  of  highly  resistant  cases,  chemotherapy  failures,  that  the 
combination  of  fever  and  chemotherapy  seems  to  be  particularly  valuable. 
For  such  cases  I  now  administer  a  single  10  hour  fever  at  106.8°  F. 
(41.5°  C.)  at  a  time  when  there  is  a  high  hemal  concentration  of  the  sul- 
fonamide drug.  This  is  strictly  an  institutional  procedure  and  should  be 
attempted  only  by  a  well-organized  group  of  fever  therapists. 

V^  found  that  in  a  group  of  43  patients  suffering  from  resistant  gonor- 
rhea, all  of  whom  had  failed  to  respond  to  unfortified  sulfonamide  ther- 
apy, an  average  of  1.2  treatments  with  combined  chemotherapy  and 
artificial  fever  for  10  hours  effected  apparent,  complete,  clinical  remissions 
for  95.4  per  cent.  Thus  it  seems  that  the  combined  procedure  is  by  far 
the  most  potent  means  of  treating  gonorrhea;  this  method  always  is  to 
be  considered,  when  unfortified  chemotherapy  fails. 

Kendell,  Rose  and  Simpson'^  agree  with  me  because  recently  they  re- 
ported: "All  of  31  unselected  consecutive  patients  treated  with  sulfanil- 
amide or  promin  for  eighteen  hours  before  a  single  10  hour  fever  session 
at  a  rectal  temperature  of  106.6°  F.  were  cured."  They  studied  83  patients 
suffering  from  complications  of  gonorrhea,  resistant  or  intolerant  to  chemo- 
therapy. "Of  those  refractory  patients,  receiving  fever  therapy  alone, 
only  12.5  per  cent,  were  cured  following  a  single  8  hour  treatment  at 
106.6°  F.;  62.5  per  cent,  were  cured  following  a  single  10  hour  treatment 
at  106.6°  F." 

I  have  been  using  the  10  hour  sessions  of  fever  at  approximately 
106.8°  F.  (41.5°  C.)  routinely  for  resistant  gonorrhea  since  January  1937, 
because  previously  I  had  come  to  the  conclusion  that  this  was  the  most 
satisfactory  way  of  treating  resistant  gonorrhea.  The  observations  of 
Kendell  and  his  associates  confirm  these  views. 

With  the  introduction  of  chemotherapy  this  procedure  was  combined 
with  the  10  hour  sessions  of  fever  with  even  better  results.  Kendell  and 
his  associates  observed  that  "a  10  day  period  of  intensive  sulfanilamide 
therapy  prior  to  fever  therapy  is  without  value  in  sulfanilamide-resist- 
ant  patients,  provided  none  of  the  drug  is  present  in  the  body  fiuids  at 
the  time  of  the  fever  treatment."  This  confirms  my  previous  contention 
that  there  must  be  a  high  hemal  concentration  of  the  drug  at  the  time  of 
the  fever  treatment. 

Kendell  and  his  associates  came  to  a  conclusion  with  which  I  agree; 
namely,  that:  "The  combination  of  a  single  10  hour  session  of  artificial 
fever  therapy  combined  with  the  administration  of  adequate  sulfanila- 
mide or  promin  for  eighteen  hours  prior  to   the  fever  treatment  appears 

Vol.  I.  941 


776  PHYSICAL   MEDICINE 

to  be  the  procedure  of  choice  in  the  treatment  of  chemotherapy-resistant 
gonococcic  infections." 

Gonorrheal  Arthritis. — Fever  therapy  is  the  most  effective  means  of 
treatment  for  gonorrheal  arthritis.  In  the  "Fifth  Rheumatism  Review"* 
there  was  a  summary  of  fifteen  reports  in  which  results  of  fever  therapy 
in  approximately  380  cases  of  gonorrheal  arthritis  were  presented.  About 
90  per  cent,  of  these  380  patients,  who  had  acute  or  chronic  gonorrheal 
arthritis,  became  free  of  symptoms.  Fever  therapy  was  spoken  of  var- 
iously as  "specific",  "the  procedure  of  choice",  "the  best  treatment  now 
available"  and  "the  treatment  of  choice  to  be  used  at  the  earliest  avail- 
able opportunity"  in  cases  of  gonorrheal  arthritis. 

Recent  advances  in  chemotherapy  undoubtedly  have  lessened  the  in- 
cidence of  this  later  manifestation  of  gonorrhea.  But  whenever  chemo- 
therapy fails  to  prevent  the  development  of  a  gonorrheal  arthritis,  the 
combined  fever-chemotherapy  regimen  should  be  attempted  at  once.  It 
is  unwise  to  delay  the  combined  procedure  too  long,  because  the  earlier 
the  combined  treatment  is  given,  the  less  is  the  likelihood  of  permanent 
damage  to  the  involved  joint  or  joints. 

Gonococcal  Septicemia.  —  There  have  been  several  reports'^-  ^°'  ^^'  -^  of 
cases  of  gonococcal  septicemia  in  which  cure  followed  fever  therapy.  In 
two  instances^^'  ^^,  even  though  there  was  an  associated  gonococcal  endo- 
carditis, recovery  occurred.  In  Elkins'  and  my-^  case  of  gonococcal 
endocarditis,  in  which  fever  therapy  was  used,  recovery  did  not  occur. 
In  the  light  of  present  knowledge  the  combination  of  fever  and  chemo- 
therapy always  should  be  considered  when  gonococcal  septicemia  is 
encountered. 

Meningococcal  Septicemia.  —  For  this  condition  combined  fever  and 
chemotherapy  may  be  curative.  Elkins  and  I'-^  reported  successful  em- 
ployment of  this  procedure  in  one  such  case.  Four  cases  of  meningococcal 
septicemia,  in  which  unfortified  fever  therapy  has  produced  cures,  have 
been  reported'-'*'  -^.  The  combined  procedure  seems  worthy  of  trial  in 
selected  cases  of  meningococcal  infection. 

Multiple  Sclerosis.  —  Fever  therapy,  although  often  recommended, 
seems  to  be  of  limited,  if  of  any,  value  for  multiple  sclerosis.  After 
treating  10  patients  with  discouraging  results,  I  abandoned  the  procedure. 
A  review  of  the  conclusions  of  five  other  investigators^-  -*~-^  led  to  the 
conclusion  that  the  results  of  fever  therapy  for  multiple  sclerosis  for  the 
most  part  have  been  unfavorable^^.  Recently  Bennett  and  Lewis^" 
checked  51  cases  of  multiple  sclerosis  for  an  average  of  thirty-one  months 
after  artificial  fever  therapy.  Although  they  expressed  the  opinion  that 
the  procedure  still  should  be  tried  early,  when  the  patients  were  "ambu- 

VoL.  I.  941 


ACTION   AND   USES  OF   FEVER   THERAPY  777 

latory  without  assistance",  they  concluded  that  "on  the  whole,  except  in 
the  early  group  of  cases  and  those  having  signs  which  suggest  infection, 
there  is  little  evidence  that  fever  therapy  has  any  markedly  beneficial 
results  in  multiple  sclerosis".  Furthermore  they  stated  that  in  "the 
bedridden  group",  fever  therapy  "does  no  good  and  may  do  harm". 

Mycosis  Fungoides,  Neuritis  and  Radicular  Pain.  —  Fever  therapy  has 
been  employed  in  treatment  of  mycosis  fungoides  with  transitory  improve- 
ment. Of  10  cases  reported  in  the  literature^^- ^^  moderate  and  temporary 
improvement  was  noted  in  8.  I  have  seen  temporary  but  distinct  im- 
provement in  2  cases.  Fever  therapy  may  retard  the  disease  sufficiently 
to  warrant  its  employment. 

For  neuritis  and  radicular  pain  artificial  fever  of  low  temperature  has 
been  recommended^^  as  a  safe  and  efficient  means  of  treatment. 

Rheumatic  Fever.  —  Treatment  for  rheumatic  fever  by  means  of  phys- 
ical fevers,  especially  when  combined  with  chemotherapy,  sometimes  may 
be  justifiable.  In  one  series  of  cases^*  there  often  was  relief  from  pain  and 
from  swelling  of  joints  as  well  as  a  final  reduction  in  the  number  of  leu- 
kocytes and  in  the  sedimentation  rate  of  the  erythrocytes.  In  two-thirds 
of  this  small  series  of  9  cases  inactivity  occurred  in  an  average  of  24  days 
after  an  average  of  5  fever  treatments. 

Syphilis.  —  Investigations^*  of  the  treatment  for  early  syphilis  by 
physically  induced  fevers  revealed  that  artificial  fevers  combined  with 
antisyphilitic  chemotherapy  afford  better  results  than  can  be  obtained 
from  the  use  of  either  one  alone.  In  an  experimental  study-  of  the  com- 
bined procedure  for  treatment  of  early  syphilis  it  was  found  that  arti- 
ficial fever  fortifies  and  intensifies  the  curative  action  of  chemotherapeutic 
agents  and  that  the  time  required  for  treatment  can  be  reduced  greatly  by 
the  combined  treatment  method.  In  its  present  stage  of  development 
fever  therapy  cannot  possibly  be  made  available  to  the  average  patient, 
who  has  a  primary  syphilitic  lesion,  but  it  is  possible  that  it  may  be 
employed  routinely  for  primary  syphilis  at  some  future  time.  A  final 
evaluation  of  the  procedure  will  not  be  possible  for  many  years. 

For  dementia  paralytica  physically  induced  fevers  frequently  can  be 
used  to  great  advantage.  There  still  is  much  controversy  concerning  the 
comparative  value  of  physical  fever  and  malarial  fever  in  treatment  for 
paresis.  Enthusiasts  about  malarial  fever  have  been  slow  to  recognize  the 
undoubted  effectiveness  of  physically  induced  fever  for  dementia  paralytica. 

Probably  the  most  authoritative  comparative  study  of  the  relative 
merits  of  the  two  procedures  is  that  recently  published  by  physicians 
from  a  group  of  co-operating  clinics  working  in  conjunction  with  the 
United    States    Public    Health    Service^^.      This   group,    whose    chairman 

Vol.  I.  941 


778  PHYSICAL   MEDICINE 

was  O'Leary,  carefully  studied  i,ioo  patients,  who  were  treated  with 
malaria  as  compared  with  320  patients,  who  received  physically  induced 
fevers.  The  number  of  cases  was  large  enough  to  be  of  some  statistical 
significance,  and  there  was  much  evidence  to  indicate  the  slight  superiority 
of  physical  fevers  over  malarial  fevers. 

The  Committee  studied  patients  "under  treatment-observation"  for 
three  or  more  years.  Of  the  patients,  who  had  mild  paresis,  52.4  per 
cent,  of  those  treated  with  malarial  fever  and  59.3  per  cent,  of  those  re- 
ceiving physical  fever  obtained  remissions.  Of  those  who  had  inter- 
mediate paresis  27.3  per  cent,  of  the  patients,  who  were  treated  with 
malaria,  and  28.1  per  cent,  of  those  treated  by  physical  fevers  obtained  re- 
missions. For  severe  paresis  an  even  more  striking  difference  was  found: 
only  0.8  per  cent,  of  the  malaria  treated  group  as  compared  with  12.0 
per  cent,  of  those  treated  by  physical  fevers  had  remissions.  Furthermore 
the  "crude  death  rate"  in  the  malaria  treated  group  was  13.4  as  compared 
with  only  8.1  in  the  cases  treated  with  physically  induced  fever. 

In  only  one  respect  did  the  statistical  evidence  seem  to  reveal  a  su- 
periority of  the  malarial  therapy  over  the  artificial  fever  therapy.  "In 
patients  treated  with  fever  plus  chemotherapy  the  annual  rates  of  spinal 
fiuid  as  well  as  blood  reversal  were  consistently  higher  with  malaria  than 
with  artificial  fever."  But  even  here  there  was  an  explanation  because 
"this  difference  was  assumed  to  be  due  to  the  greater  amount  of  chemo- 
therapy,  17  per  cent,  more,  administered  to  the  malaria  patients". 

More  studies,  of  course,  will  be  necessary,  but  as  evidence  piles  up, 
it  becomes  increasingly  evident  that  physical  fevers  are  equally  as  effec- 
tive, if  not  more  effective,  than  malarial  fevers  in  the  treatment  of  de- 
mentia paralytica.  In  addition  any  procedure,  which  will  lessen  the 
mortality  by  more  than  5  per  cent.,  should  be  given  careful  consideration. 

For  tabes  dorsalis  fever  therapy  sometimes  has  been  recommended. 
In  a  report^  of  the  results  of  this  treatment  of  15  patients,  8  were  said  to 
be  greatly  improved,  6  moderately  improved  and  i  was  unimproved.  One 
of  the  most  constant  results  has  been  relief  of  gastric  crises  and  tabetic 
pains.  Another  investigator'^  reported  that  two-thirds  of  114  tabetic 
patients  exhibited  definite  improvement  following  fever  therapy. 

Fever  therapy  has  been  reported  also  as  being  of  much  value  in  the 
treatment  of  ocular  syphilis.  Culler^^  found  the  combination  of  fever  and 
chemotherapy  useful  for  syphilitic  interstitial  keratitis,  exudative  uveitis 
and  choroiditis. 

Tetanus.  —  An  interesting  case  in  which  fever  therapy  was  employed 
in  my  department  as  an  adjunct  in  treatment  for  tetanus  was  reported 
recently  by  Heersema^^.     In  this  case  fever  therapy  was  administered  in 

\'oL.  I.  941 


ACTION   AND   USES   OF   FEVER   THERAPY  779 

conjunction  with  the  use  of  antitoxin.  Despite  the  fact  that  he  had  failed 
previously  to  respond  to  large  doses  of  antitoxin,  when  fever  therapy  was 
inaugurated,  the  patient  began  to  improve,  and  he  finally  recovered. 
Heersema  commented  that;  "it  is  not  impossible  to  postulate  a  more 
effective  interrelationship  of  the  toxin  and  antitoxin  facilitated  by  the 
hyperthermia.  For  the  present,  however,  the  symptomatic  relief  obtained 
is  sufficient  to  warrant  further  trial  of  this  method.  There  was  no  doubt 
of  this  patient's  improvement  by  the  third  day  of  treatment,  whereas  the 
clinical  course  before  initiation  of  hyperthermia  was  definitely  downward." 

Malignant  Tumors.  —  Warren'''^  of  Rochester,  New  York,  has  em- 
ployed a  combination  of  roentgen  therapy  and  physical  fever  in  treatment 
of  malignant  tumors.  He  stated  that  the  growth  of  tumors  is  inhibited 
more  completely  by  the  combined  procedure  than  by  roentgen  therapy 
alone.  Jares^",  also  working  at  Rochester,  New  York,  studied  the  thermal 
death  time  of  animal  tumor  cells  in  vitro.  He  came  to  the  conclusion 
that  the  combined  effects  of  fever  and  roentgen  rays  are  superior  to  the 
effect  of  either  alone.  The  most  destructive  combination  was  simple, 
fractional  doses  of  roentgen  rays,  about  300  r.  daily,  plus  fever  treatment 
immediately  afterward. 

In  a  recent  report^^  on  the  studies  at  Rochester,  New  York,  on  the 
combined  effects  of  high  voltage  roentgen  therapy  and  artificial  fever  on 
carcinoma  the  author  stated;  "The  summative  effects  of  the  two  radia- 
tions, x-rays  and  heat,  appear  to  be  more  destructive  to  the  carcinoma  and 
normal  structures  than  either  alone.  Since  the  dosage  values  are  not  well 
understood  the  experiments  have  been  restricted  to  hopeless  cases.  The 
delayed  effects  (telangiectases,  edema,  cutaneous  degeneration  and  the 
like)  seem  to  be  more  marked,  probably  because  of  the  summative  effect. 

"The  following  dosage  has  been  used  with  safety,  though  it  should 
not  be  attempted  by  any  one  not  well  versed  in  both  irradiation  technic 
and  fever  treatment  technic:  Daily  for  six  days  250  roentgens  is  given  in 
the  usual  manner  for  any  one  port.  On  the  third  day  in  this  schedule  a 
five  hour  fever  bout  at  41.5°  C.  (106.7°  ?"•).  rectal  temperature  is  admin- 
istered and  at  the  end  of  the  fever,  while  the  body  temperature  is  up, 
that  day's  x-ray  treatment  is  given.  A  second  fever  bout  of  one  hour 
(or  more  if  the  patient  is  not  too  much  intoxicated  by  the  tumor  destruc- 
tion) is  given  on  the  fifth  day  with  the  x-ray  treatment  again  adminis- 
tered at  its  end.  Several  portals  may  be  treated  simultaneously  except 
that  great  caution  must  be  exercised  not  to  overtreat  (i.e.  not  over  1,800 
roentgens  given  to  any  one  skin  area)  within  a  given  course.  Courses 
have  been  repeated  in  six  months  without  catastrophe,  although  the  dam- 
age to  the  skin  was  considerable. 

Vol.  I.  941 


78o  PHYSICAL   MEDICINE 

"At  present  this  method  is  purely  experimental  and  is  not  advocated 
for  general  use  until  its  merits  are  more  clearly  defined." 

At  this  time,  there  is  no  indication  for  the  clinical  employment  of  fever 
therapy  as  a  therapeutic  measure  for  malignant  tumors. 

Undidant  Fever  {Brucellosis).  —  Fever  therapy  has  proved  to  be  of 
distinct  value  in  treatment  for  undulant  fever.  Prickman,  Bennett  and 
P'  reviewed  the  results  obtained  in  21  cases  of  brucellosis  following 
treatment  by  means  of  physically  induced  fever  and  found  that  in  ap- 
proximately 80  per  cent,  apparently  complete  clinical  remissions  occurred. 
Recently  Moor^^  reported  on  15  cases  of  brucellosis  treated  by  fever  ther- 
apy. Nine  patients,  60  per  cent.,  obtained  "unqualified  recovery";  one  was 
"much  improved";  one  was  "improved",  and  the  other  four  were  only 
"temporarily  improved".  Zeiter'*^  at  the  Cleveland  Clinic  and  several 
others^^  also  have  reported  successful  treatment  of  brucellosis  by  means  of 
fever  therapy.  Results  have  been  most  encouraging  throughout;  although 
the  series  still  is  small,  there  is  increasing  evidence  of  the  value  of  fever 
therapy  in  this  disease. 

Contraindications  to  the  General  Application  of  Heat 
(Fever   Therapy) 

Serious  complications  of  fever  therapy  are  heat  stroke,  heat  exhaustion 
and  circulatory  collapse,  which  are  followed  by  anoxia  and  finally  hemor- 
rhagic changes  and  damage  to  nerve  tissues.  Minor  complications  in- 
clude tetany,  heat  cramps,  delirium,  mild  dehydration  with  resultant 
nausea  and  vomiting,  superficial  burns  and  herpes  labialis.  Skillful  treat- 
ment will  prevent  or  minimize  many  of  these  complications.  Important 
factors  in  management  include  the  administration  of  sufificient  amounts  of 
fluid  either  orally  or  intravenously  to  prevent  circulatory  collapse,  the 
employment  of  inhalations  of  oxygen  throughout  the  treatment  in  order 
to  prevent  anoxia  and  proper  cooling  of  the  patient  in  case  the  tempera- 
ture becomes  too  high. 

Apparently  several  deaths  have  occurred  because  of  incorrect  attempts 
at  lowering  bodily  temperature  during  excessive  hyperpyrexia.  In  several 
instances  patients  have  been  placed  in  ice  packs  in  an  attempt  to  lower 
rapidly  their  high  systemic  temperatures.  Actually  this  procedure  con- 
stricts the  peripheral  capillaries,  lessens  the  amount  of  radiation  of  heat,. 
drives  the  hot  blood  from  the  surface  into  the  splanchnic  regions  and 
often  causes  a  slight  additional  rise  of  the  rectal  temperature.  The  cor- 
rect method  of  lowering  the  bodily  temperature,  if  it  becomes  too  high, 
consists  of  removing  the  patient  from  the  fever  producing  device,  sponging 

Vol.  I.  941 


SUMMARY   OF   FEVER   THERAPY  781 

his  nude  body  with  tepid  water  and  turning  a  fan  so  that  it  blows  across 
the  surface  of  the  body.  Bodily  heat  thus  will  be  dissipated  rapidly  by 
evaporation,  and  the  hitjh  temperature  will  tend  to  fall  rapidly  to  normal. 

A  treatment  as  heroic  as  fever  therapy  is  not  without  a  definite  ele- 
ment of  danger.  According  to  the  most  accurate  compilation  I  have  been 
able  to  make  the  mortality  rate  per  patient  from  fever  therapy  now  is 
less  than  0.2  per  cent.  This  compares  favorably  with  the  mortality  from 
simple  appendectomy.  In  one  average  hospital,  685  appendectomies  were 
performed  and  there  were  8  deaths,  a  percentage  mortality  rate  per  pa- 
tient of  1. 1 6. 

Fever  therapy  is  contraindicated  in  about  the  same  conditions  as  is  a 
major  operation.  It  should  not  be  administered  to  patients  who  have 
severe  cardiovascular-renal  disease,  evidences  of  damage  to  the  liver  or 
sensitivity  to  heat.  Its  employment  is  contraindicated  at  the  extremes 
of  age.  The  very  young  and  the  very  old  do  not  tolerate  fever  therapy 
well.  It  always  should  be  used  with  caution  for  patients  who  are  asthenic 
or  dehydrated.  A  careful  general  physical  examination  and  accurate 
laboratory  studies  should  be  performed  before  administration  of  fever 
therapy. 

Summary  of  Data  on  Fever  Therapy 

There  are  numerous  effective  methods  for  the  general  application  of 
heat  to  the  human  body.  The  procedure  usually  is  called  "fever  ther- 
apy". Elevations  of  systemic  temperature  can  be  accomplished  by 
means  of  heated  cabinets,  diathermy,  hot  baths  or  by  heated  blankets  or 
packs.  The  hot  humid  air  cabinet  seems  to  be  the  most  satisfactory 
device  for  producing  artificial  fever  by  physical  means. 

High  artificial  fevers  produce  profound  physiological  changes  which 
have  been  investigated  rather  extensively  in  the  past  few  years.  Fever 
therapy  has  become  a  therapeutic  agent  of  considerable  usefulness,  and  it 
gives  promise  of  being  still  more  valuable  as  more  information  is  ascer- 
tained concerning  it. 

Fever  therapy  often  is  of  value  in  treatment  for  resistant  gonorrhea 
and  its  complications  and  for  syphilis  and  its  various  forms.  The  value  of 
fever  therapy  for  syphilis  of  the  nervous  system  is  becoming  recognized. 
It  has  been  employed  also,  to  more  or  less  advantage,  in  the  management 
of  atrophic  arthritis,  intractable  bronchial  asthma,  Sydenham's  chorea, 
endocarditis  lenta,  meningococcal  septicemia,  mycosis  fungoides,  neuritis, 
rheumatic  fever,  tetanus  and  undulant  fever.  The  combined  application 
of  fever  and  chemotherapy  apparently  is  going  to  be  extremely  useful  in 

Vol.  I.  941 


782  PHYSICAL   MEDICINE 

a  number  of  diseases.  Fever  therapy  requires  a  trained  personnel  and 
proper  equipment.  In  unskilled  hands  the  procedure  is  potentially  ex- 
tremely dangerous.  The  development  of  fever  therapy  is  a  distinctly 
valuable  contribution  to  the  advance  of  modern  therapeutics. 

BIBLIOGRAPHY   OF   FEVER   THERAPY 

1.  SIMPSON,  W.  M.  and  KENDELL,  H.  W.:   Artificial  fever  therapy,  Colorado 

Med.,   1937,  XXXIV,  782. 

2.  SIMPSON,  W.  M.  and  KENDELL,  H.  W.:    Experimental  treatment  of  early 

syphilis  with  artificial  fever  combined  with  chemotherapy,  pp.  143-145, 
in  Fever  Therapy;  abstracts  and  discussions  of  papers  presented  at  the 
First    International    Conference   on    Fever   Therapy,    Hoeber,    New   York, 

1937- 

3.  BISHOP,  F.  \V.,  LEHMAN,  E.  and  WARREN,  S.  L.:   A  comparison  of  three 

electrical  methods  of  producing  artificial  hyperthermia.  Jour.  Am.  Med. 
Assoc,  1935,  CIV,  910. 

4.  ATSATT,    R.   F.  and    PATTERSON,  L.  E.:    Fever  therapy  apparatus,  Arch. 

Phys.  Therapy,  1936,  XVII,  108. 

5.  HALPHEN,  A.  and  AUCLAII^,  J.:    Short  waves;   a  perfect  pyretogenic  agent, 

pp.  21-23,  in  Fever  Therapy;  abstracts  and  discussions  of  papers  presented 
at  the  First  International  Conference  on  Fever  Therapy,  Hoeber,  New 
York,   1937. 

6.  HENCH,   P.   S.,   BAUER,  W.,  DAWSON,  M.  H.,  HALL,  F.,  HOLBROOK, 

W.  P.  and  KEY,  J.  A.:  The  problem  of  rheumatism  and  arthritis;  review 
of  American  and  English  literature  for  1937  (fifth  rheumatism  review),  Ann. 
Int.  Med.,  1939,  XII,  1005,  1295. 

7.  NEYMANN,  C.  A.:    Artificial  Fever  Produced  by   Physical   Means;    its  De- 

velopment and  Application,  Thomas,  Springfield,  Illinois,  1938. 

8.  LICHTMAN,  S.  S.  and  BIERMAN,  W.:   The  treatment  of  subacute  bacterial 

endocarditis.  Jour.  Am.   Med.  Assoc,   1941,  CXVI,  286. 

9.  KRUSEN,  F.  H.:    The  present  status  of  fever  therapy  produced  by  physical 

means.  Jour.  Am.  Med.  Assoc,  1936,  CVII,  1215. 

10.  DRY,  T.  J.  and  WILLIUS,  F.  A.:    Fever  therapy  for  subacute  bacterial  endo- 

carditis, Proc.  Staff  Meet.,  Mayo  Clin.,  1937,  XII,  321. 

11.  BIERMAN,  \V.,  and  BAEHR,  C:    The  use  of  physically  induced  pyrexia  and 

chemotherapy,  Jour.  Am.  Med.  Assoc,  1941,  CXVI,  292. 

12.  KRUSEN,  F.  H.  and  BENNETT,  R.  L.:    Unsuccessful  treatment  of  subacute 

bacterial  endocarditis  with  combined  fever  and  sulfanilamide  therapy, 
Proc.  Staff  Meet.,  Mayo  Clin.,  1940,  XV,  328. 

13.  WHITE,  H.  J.:    The  relationship  between  temperature  and  the  streptococcidal 

activity  of  sulfanilamide  and  sulfapyridine  in  vitro.  Jour.  Bact.,  1939, 
XXXVIII,  549- 

14.  KRUSEN,  F.  H.,  RANDALL,  L.  M.  and  STUHLER,  L.:   Fever  therapy  plus 
Vol.  L  941 


BIBLIOGRAPHY  783 

additional  local  heating  in  the  treatment  of  gonococcic  infections,  pp.  168- 
170,  in  Fever  Therapy;  abstracts  and  discussions  of  papers  presented  at  the 
First  International  Conference  on  Fever  Therapy,  Hoeber,  New  York,  1937. 

15.  KRUSEN,   F.   H.:    Summary  of  results  of  fever  therapy  for  gonorrhea  with 

follow-up  reports,  Proc.  Staff  Meet.,  Mayo  Clin.,   1938,  XIII,  297. 

16.  KRUSEN,   F.   H.:    Physical   Medicine,   Saunders,   Philadelphia,    1941. 

17.  DEES,  J.  E.  and  YOUNG,  H.  H.:    Present  status  of  sulfanilamide  therapy  in 

gonorrhea,  Ven.  Dis.   Inform.,   1939,  XX,  33. 

18.  KENDELL,  H.  W.,  ROSE,  D.  L.  and  SIMPSON,  VV.  M.:   Combined  artificial 

fever-chemotherapy  in  gonococcic  infections  resistant  to  chemotherap\-. 
Jour.  Am.  Med.  Assoc,  1941,  CXVI,  357. 

19.  FREUXD,  H.  A.  and  ANDERSON,  W.  L.:    Recovery  in  a  case  of  gonococcic 

endocarditis  treated  by  artificial  hyperpyrexia,  pp.  178-180,  in  Fever 
Therapy;  abstracts  and  discussions  of  papers  presented  at  the  First  Inter- 
national Conference  on  Fever  Therapy,   Hoeber,   New  York,    1937. 

20.  HAZEL,  O.  G.  and  SNOW,  W.  B.:    Gonococcic  septicemia  with  purpura  and 

arthritis  successfully  treated  by  hyperthermia.  Jour.  Am.  Med.  Assoc, 
1937,   CIX,    1275. 

21.  WARREN,  S.  L. :    Personal  communication  to  the  author. 

22.  WILLIAMS,    R.    H.:     Gonococcal    endocarditis    treated    with    artificial    fever 

(Kettering  hypertherm),  Ann.  Int.  Med.,   1937,  X,   1766. 

23.  KRUSEN,  F.  H.  and  ELKINS,  E.  C:    Fever  therapy  for  gonococcemia  and 

meningococcemia  with  associated  endocarditis;  report  of  two  cases,  Proc. 
Staff  Meet.,  Mayo  Clin.,  1937,  XII,  324. 

24.  BENNETT,  A.   E.,   PERSON,  J.   P.  and  SIMMONS,   E.    E.:    Treatment  of 

chronic  meningococcic  infections  by  artificial  fever,  Arch.  Phys.  Therapy, 
1936,  XVII,   743. 

25.  PLATOU,  E.  S.,  McELMEEL,  E.  and  STOESSER,  A.:   Artificial  fever  in  the 

treatment  of  meningococcus  infection,   Minnesota  Med.,   1936,  XIX,  781. 

26.  WALTHARD,  K.  M.  and  HERTENSTEIN,  H.:   Some  remarks  on  short  wave 

fever  therapy,  pp.  118-119,  in  Fever  Therapy;  abstracts  and  discussions  of 
papers  presented  at  the  First  International  Conference  on  Fever  Therapy, 
Hoeber,  New  York,  1937. 

27.  DESJARDINS,  A.  U.  and  POPP,  W.  C:    Our  experience  with  iever  therapy, 

pp.  7-8,  In  Abstracts  of  Papers  and  Discussions,  Fifth  Annual  Fever 
Conference,  May  2  and  3,  1935. 

28.  BENNETT,  A.  E.  and  AUSTIN,  B.:    Preliminary  report  of  the  Universit>-  of 

Nebraska  fever  research  project,  pp.  23-24,  in  Abstracts  of  Papers  and 
Discussions,  Fifth  Annual  Fever  Conference,  May  2  and  3,  1935. 

29.  HEFKE,  H.  W. :    Report  on  the  first  year  of  fever  therapy  at  the  Milwaukee 

hospital,  pp.  29-30,  in  Abstracts  of  Papers  and  Discussions,  Fifth  Annual 
Fever  Conference,  May  2  and  3,  1935. 

30.  BENNETT,  A.   E.  and  LEWIS,   M.   D.:    Artificial  fever  therapy  in  multiple 

sclerosis;    a  study  of  fifty-one  cases,  Jour.   Nerv.  and  Ment.   Dis.,    1940, 
XCII,  202. 
Vol.  I.  941 


784  PHYSICAL   MEDICINE 

31.  KLAUDER,    J.    v.:     Fever    therapy    in    mycosis    fungoides,    Jour.  Am.  Med. 

Assoc,  1936,  CVI,   201. 

32.  PEYRI,  J.:    Quelques  commentaires  a  notre  casuistique  de  mycosis  fungoides, 

Ann.  de  Dermat.  et  Syph.,  1935,  VI,  481. 

33.  BENNETT,  A.  E.  and  CASH,  P.  T.:    The  reUef  of  neuritic  pain  by  artificial 

fever  therapy;  results  obtained  in  40  cases,  pp.  91-92,  in  Fever  Therapy; 
abstracts  and  discussions  of  papers  presented  at  the  First  International 
Conference  on  Fever  Therapy,  Hoeber,  New  York,  1937. 

34.  SIMMONS,  E.  E.:    Value  of  fever  therapy  in  the  arthritides.  Am.  Jour.  Med. 

Sci.,  1937,  CXCIV,  170. 

35.  NEYMANN,  C.  A.,  LAWLESS,  T.  K.  and  OSBORNE,  S.  L.:   The  treatment 

of  early  syphilis  with  electropyrexia.  Jour.  Am.  Med.  Assoc,  1936,  CVI  I, 
194. 

36.  O'LEARY,  P.  A.,  BRUETSCH,  W.  L.,  EBAUGH,  F.  G.,  SIMPSON,  W.  M., 

SOLOMON,  H.  C,  WARREN,  S  L.,  VONDERLEHR,  R.  A.,  USILTON, 
L.  J.  and  SOLLINS,  I.  V.:  Malaria  and  artificial  fever  in  the  treatment 
of  paresis.  Jour.  Am.  Med.  Assoc,  1940,  CXV,  677. 

37.  CULLER,   A.    M.:    Artificial   fever   therapy   of   ocular   syphilis,    pp.    105-106, 

in  Abstracts  of  Papers  and  Discussions,  Fifth  Annual  Fever  Conference, 
May  2  and  3,   1935. 

38.  HEERSEMA,  P.  H.:    Management  of  tetanus  with  report  of  use  of  hyperther- 

mia in  one  case,  Minnesota  Med.,  1940,  XXIII,  636. 

39.  WARREN,  S.  L. :    Preliminary  study  of  the  effect  of  artificial  fever  upon  hope- 

less tumor  cases.  Am.  Jour.  Roentgenol.,   1935,  XXXIII,  75. 

40.  JARES,  J.  J.,  Jr.:    The  in  vitro  thermal  death    time  of  animal  tumor  cells, 

pp.  114-115,  in  Fever  Therapy;  Abstracts  and  Discussions  of  Papers  Pre- 
sented at  the  First  International  Conference  on  Fever  Therapy,  Hoeber, 
New  York,    1937. 

41.  QUERIES  AND  MINOR  NOTES:    Combined  fever  and  roentgen  therapy  for 

cancer.  Jour.  Am.  Med.  Assoc,  1940,  CXV,  2106. 

42.  PRICKMAN,   L.   E.,   BENNETT,  R.   L.  and  KRUSEN,  F.  H.:    Treatment 

of  brucellosis  by  physically  induced  hyperpyrexia,  Proc  Staff  Meet.,  Mayo 
Clin.,  1938,  XIII,  321. 

43.  MOOR,  F.  B.:    Personal  communication  to  the  author. 

44.  ZEITER,    W.   J.:    Treatment   of   undulant   fever   by   artificial   fever   therapy, 

Cleveland  Clinic  Quart.,  1937,  IV,  309. 

Sept.  I,  1941. 


Vol.  I.  941 


METHODS  OF  APPLYING   COLD  785 

LOCAL  AND   GENERAL  APPLICATIONS  OF   COLD 

Applications  of  cold  both  locally  and  generally  have  been  employed 
for  therapeutic  purposes.  There  has  been  considerably  less  investigation 
of  hypothermy  than  of  hyperthermy.  The  therapeutic  administration  of 
cold  has  been  called  "cryotherapy"  or  "crymotherapy ",  and  prolonged 
systemic  applications  of  cold  have  been  spoken  of  as  "hibernation"  or 
' '  refrigeration  therapy  " . 

Recently  considerable  unfortunate  publicity  has  been  given  to  the 
possibilities  of  benefiting  carcinoma  by  such  general  applications  of  cold. 
As  yet  there  is  no  convincing  evidence  that  any  such  possibility  does 
exist.  While  studies  in  a  few  cases  have  indicated  that  prolonged  general 
applications  of  cold  effect  apparent  modifications  in  malignant  cells,  the 
number  of  cases  studied  is  so  meager  as  to  preclude  serious  consideration 
at  this  time. 

Although  local  applications  of  cold  long  have  been  used  in  therapy, 
the  general  application  of  cold  has  not  been  established  as  yet  as  a  rational 
therapeutic  procedure. 

Methods  of  Applying  Cold 

Cold  water  or  ice  can  be  applied  directly  or  indirectly  to  a  small  or 
large  area  of  the  human  body  to  produce  local  or  systemic  effects.  In 
some  instances  ordinary  refrigerating  units,  similar  to  those  employed  in  the 
household,  electrical  iceboxes,  are  connected  with  metallic  coils  or  blankets, 
which  are  applied  to  the  entire  body  of  the  patient  in  order  to  effect 
lowering  of  the  systemic  temperature. 

In  other  instances  an  air  cooling  unit,  similar  to  that  employed  for 
air  conditioning  of  rooms  in  the  summer,  is  employed  to  cool  a  small 
room,  in  which  the  nude  patient  lies  on  a  bed,  in  order  that  his  systemic 
temperature  may  be  lowered.  Another  arrangement,  which  I  have  seen, 
consisted  of  a  cold  air  blower  connected  to  the  top  of  a  tent  which  was 
placed  over  the  bed  of  the  patient.  The  cold  air  blew  down  over  the 
patient  and  cooled  him  effectively.  In  still  another  arrangement  the  pa- 
tient is  placed  in  a  large  bag  containing  within  its  walls  serpentine  coils, 
through  which  is  circulated  a  cooling  fluid  derived  from  a  regular  refrig- 
eration unit,  which  is  placed  at  the  foot  of  the  patient's  bed. 

For  local  application  of  cold  the  time-honored  ice  bag,  the  cold  com- 
press and  the  ice  pack  still  are  extremely  useful.  A  refinement  of  technic 
consists  of  the  construction  of  sets  of  metallic  applicators,  which  can  be 
connected  to  a  refrigeration  unit  and  through  which  the  refrigerating  mix- 

VoL.  I.  941 


786 


PHYSICAL   MEDICINE 


ture  is  circulated  (Fig.  i6).  These  small  applicators  can  be  applied  to 
various  regions  or  orifices  of  the  body  in  order  to  administer  intense  cold. 
Little  is  known,  as  yet,  concerning  the  value  of,  or  indications  for,  the 
use  of  these  applicators,  which  were  constructed  primarily  for  use  in  con- 
junction with  "hibernation  therapy"  for  malignant  lesions.    The  thought 


Fig.    1 6.    Applicators  through   which   a  cooling   mixture    can    be   circulated    from  a 
refrigeration  unit  to  permit  local  applications  of  intense  cold. 


was  that  these  applicators  could  be  applied  directly  over  the  growth  to 
produce  additional  local  cooling  during  the  period  when  the  bodily  tem- 
perature was  lowered. 

I  have  had  no  personal  experience  with  the  methods  for  treatment  of 
malignant  lesions  by  means  of  general  and  local  applications  of  cold  and 
sincerely  doubt  that  the  procedures  ever  will  be  of  much,  if  of  any,  value. 
Nevertheless  it  seems  worth  while  to  consider  the  whole  subject  of  cold 

Vol.  I.  941 


ACTION   AND    USES  OF   COOLING   PROCEDURES        787 

therapy,  because  there  have  been  so  many  recent  inquiries  concerning  it, 
and  because  its  distinct  hmitations  should  be  stated. 

Physical  Principles  Concerned  in  the  Application  of  Cold 

There  is  an  extreme  dearth  of  information  concerning  the  physics  of 
cold.  Textbooks  on  physics  neglect  this  subject  in  an  amazing  fashion. 
From  a  therapeutic  standpoint,  however,  it  is  necessary  merely  to  know 
that,  in  order  to  apply  cold  to  all,  or  to  a  part,  of  the  human  body,  it 
must  be  placed  in  a  cold  environment  or  in  contact  with  a  cold  sub- 
stance. 


Action  and  Uses  of  Cooling  Procedures 

Cooling  of  the  surface  of  the  body  without  compensation  produces 
definite  systemic  changes.  Constriction  of  the  peripheral  vessels  occurs 
with  associated  peripheral  stasis  and  anoxemia.  There  is  a  lowered 
leukocytic  response,  and  the  phagocytic  capability  of  the  fixed  tissue  cells 
is  impaired.  These  changes  are  the  reverse  of  those  observed  on  applica- 
tions of  heat.  Processes  of  immunity  unquestionably  are  delayed  in  local 
regions  which  are  cooled.  Locally  the  volume  of  blood  will  be  diminished, 
and  local  metabolic  activity  will  decrease.  Application  of  cold  to  the 
abdomen  tends  to  cause  a  temporary  increase  in  peristalsis,  which  is 
followed  later  by  a  decrease. 

Placing  the  forearm  in  cold  water  lessens  the  rate  of  circulation  so 
greatly  that  eventually  even  comparatively  deep  tissues  may  have  a 
temperature  little  higher  than  that  of  the  bath.  Local  application  of 
cold  to  any  region  of  the  body  will  tend  to  cause  generalized  vasocon- 
striction.    Drinking  of  cold  water  likewise  causes  vasoconstriction. 

Hypersensitivity  to  cold  occasionally  is  observed.  Horton  and  his 
associates^  studied  22  hypersensitive  persons  and  noted  that  locally  there 
was  cutaneous  pallor  during  exposure;  redness,  swelling  and  increased  local 
temperature  appeared  on  removal  from  the  cold  environment.  After  a 
latent  period  of  three  to  six  minutes  the  systemic  reaction  developed; 
this  consisted  of  flushing  of  the  face,  a  sharp  drop  in  blood  pressure,  a 
rise  in  pulse  rate,  a  tendency  toward  syncope  and  then  transitory  recovery 
in  five  or  ten  minutes.  These  studies  suggested  that  a  chemical  substance, 
which  causes  a  histamine-like  reaction,  is  produced  in  the  skin  following- 
exposure  to  cold. 

Although  in  most  instances  applications  of  cold  impair  circulation, 
occasionally  applications  of  mild  cold,  which  will  cause  slight  vascular  con- 

VoL.  I.  941 


788  PHYSICAL   MEDICINE 

striction  and  moderate  reduction  of  capillary  pressure,  actually  may  cause 
a  more  rapid  flow  of  blood  than  would  application  of  heat. 

Reactions  to  thermal  changes  are  very  complex.  They  are,  in  general, 
vasodilatation  on  heating  and  vasoconstriction  on  cooling.  If  the  cold  is 
intense,  it  may  cause  vasodilatation.  Arterioles,  capillaries,  arteriovenous 
aneurysms  and  veins  are  involved.  There  may  be  considerable  local  in- 
crease or  decrease  in  the  flow  of  blood.  These  changes  are  caused  partly 
through  nervous  reflexes.  Application  of  cold  to  an  extremity  may 
cause  vasoconstriction  in  a  distant  region  such  as  an  opposite  limb  which 
is  not  primarily  affected  by  the  change  in  temperature. 

Peripheral  vasoconstriction  caused  by  local  application  of  cold  is 
balanced  by  opposite  changes  in  the  remaining  vessels,  particularly  the 
splanchnic  or  other  deep  vessels.  Bazetf-  has  shown  that  the  vasodila- 
tation caused  by  extreme  cold  occurs  only  when  the  temperature  of  the 
skin  is  less  than  64.4°  F.  (18°  C).  The  reflex  that  produces  such  dilata- 
tion probably  is  akin  to  a  mild  inflammatory  reaction.  This  reaction 
may  protect  the  peripheral  region  from  injury. 

Brooks  and  Duncan^  recently  have  conducted  interesting  studies 
on  the  eff^ects  of  temperature  on  the  survival  of  anemic  tissue.  These 
experiments  demonstrated  conclusively  "that  temperature  is  a  powerful 
factor  in  determining  the  length  of  time  tissues  rendered  completely 
anemic  remain  viable".  Although  usually  it  has  been  contended  that  in 
the  presence  of  threatened  gangrene  the  part  should  be  kept  in  a  warm 
environment  to  maintain  viability  and  to  promote  normal  circulation, 
these  investigators  found  that  completely  anemic  tissues  became  gangre- 
nous much  sooner  at  high  temperatures  than  at  low  ones.  Brooks  in 
discussion  stated  that  the  experiments  have  convinced  him  of  "the  in- 
advisability  of  applying  unregulated  heat  to  an  anemic  extremity  and 
have,  at  least,  raised  the  question  of  the  possible  benefits  of  the  employ- 
ment of  a  method  for  maintaining  temperature  of  anemic  tissue  below 
that  which  it  would  assume  under  ordinary  clinical  conditions".  Here, 
possibly,  is  a  new  indication  for  the  employment  of  local  applications  of 
cold. 

General  applications  of  cold  cause  distinct  changes  in  the  circulation 
time.  These  have  been  investigated  carefully  by  Oppenheimer  and  Mc- 
Cravey^.  They  observed  the  circulation  time  of  human  beings  subjected 
to  "refrigeration"  and  found  that  it  was  increased  from  an  average  of 
17.2  seconds  at  normal  bodily  temperature  to  23.5  seconds  in  the  same 
individuals  during  "hibernation".  They  observed  an  "apparent  correla- 
tion" between  prolongation  of  circulation  time  and  reduction  in  rectal 
temperature;    the   circulation   time   increased   approximately  5   per  cent. 

Vol.  I.  941 


ACTION   AND   USES  OF   COOLING   PROCEDURES        789 

for  each  degree  Fahrenheit  the  temperature  decreased.  Tlie  bleeding 
time  has  been  shown''  to  be  reduced  in  partially  frozen  animals. 

If  the  systemic  temperature  of  rabbits  is  decreased  to  less  than  75.2°  F. 
(24°  C),  frostbites  will  occur.  Shivering  ceases  at  this  temperature  level, 
and  the  lethal  general  temperature  for  rabbits  is  approximately  60.8°  F. 
(16°  C).  Oppenheimer  has  informed  me  that  human  beings  cease  to 
shiver  as  the  body  is  cooled,  and  shivering  does  not  return  as  the  body  is 
gradually  warmed  again.  Large  amounts  of  heat  are  required  to  restore 
the  normal  temperature  of  animals  or  human  beings  after  cooling.  Troeds- 
son'^  found  that,  when  the  temperature  of  rabbits  was  lowered  to  73.4°  F. 
(23°  C),  the  number  of  leukocytes  decreased  from  10,300  to  5,200  per 
cubic  millimeter;  the  relative  number  of  polymorphonuclear  leukocytes 
increased,  and  the  lymphocytes  decreased. 

Experimental  studies  by  Meader  and  Marshall^  revealed  that  mice 
were  able  to  survive  an  internal  temperature  of  47.3°  F.  (8.5°  C).  Cooling 
produces  an  initial  acceleration  of  the  respiratory  rate  which  is  followed 
by  a  reduction  of  rate.  The  respiratory  rate  diminishes  approximately 
10  excursions  per  minute  per  degree  centigrade  of  loss  of  heat,  until  an 
internal  temperature  of  53.6°  to  60.8°  F.  (12°  to  16°  C.)  is  reached. 
Thereafter  it  diminishes  approximately  20  excursions  per  minute  per 
degree  centigrade. 

Rapid  freezing  of  aqueous  suspensions  of  bacteria  leads  to  death  of  a 
constant  proportion  of  cells,  varying  from  about  80  per  cent,  of  the  most 
sensitive  organisms,  Pseudomonas  aeruginosa  {Bacillus  pyocyaneus),  to  a 
slight  percentage  or  no  destruction  of  the  least  sensitive  structures,  spores^. 

A  significant  study,  which  suggests  the  futility  of  employing  cold  as 
a  curative  agent  for  malignant  disease,  is  that  of  Breedis  and  his  asso- 
ciates^^. They  found  that  although  the  transmitting  agent  of  leukemia  in 
mice,  presumably  malignant  leukocytes,  is  inactivated  by  rapid  freezing 
to  -22°  F.  (-30°  C),  it  nevertheless  remains  viable  even  at  -94°  F. 
(-70°  C.)  when  frozen  slowly.  These  investigators  found  also  that  sarcom- 
atous tissue  of  mice  can  be  frozen  to  at  least  -94°  F.  (-70°  C.)  without 
being  inactivated,  and  that  this  tissue  can  be  preserved  at  this  tempera- 
ture with  little  or  no  subsequent  deterioration  during  at  least  56  days. 
In  the  light  of  these  facts  it  seems  that  it  is  utterly  useless  to  attempt  to 
destroy  or  to  inhibit  the  growth  of  malignant  cells  in  the  living  human 
being  by  gradual  reduction  of  the  systemic  temperature  to  levels  between 
-f88°  and  90°  F.  (-1-31.1°  and  32.2°  C.)  for  periods  of  five  or  six  days. 

Local  Applications  of  Cold.  —  These  have  been  employed  therapeuti- 
cally for  conditions  in  which  peripheral  vasoconstriction  is  desirable. 
Contusions,  sprains  or  other  superficial  traumatic  lesions,  in  which  there 

Vol.  I.  941 


790  PHYSICAL   MEDICINE 

is  danger  of  extravasation  of  blood  and  lymph  into  the  perivascular  tissues, 
often  can  be  treated  best  during  the  first  forty-eight  hours  by  local  appli- 
cations of  cold. 

Cold  often  is  applied  locally  for  acute  inflammation  or  congestion  of 
superficial  regions  in  order  to  produce  vasoconstriction  and  to  relieve  pain, 
but  cold  cannot  be  used  to  allay  inflammations  within  the  abdomen,  be- 
cause now  it  is  believed  generally  that  local  application  of  cold  to  the 
abdomen  produces  little,  if  any,  change  in  the  temperature  of  the  under- 
lying viscera.  Intense  cold  can  be  used  to  destroy  superficial  cutaneous 
lesions.     Usually  a  carbon  dioxide  pencil  is  employed  for  this  purpose. 

Occasionally  when  a  local  rise  of  temperature  in  an  extremity  is  de- 
sirable, and  a  rise  of  systemic  temperature  is  contraindicated,  the  general 
rise  can  be  avoided  by  placing  another  extremity  in  moderately  cold  water 
while  the  affected  extremity  is  being  heated.  This  is  known  as  the  Loven 
reflex. 

Patients,  who  are  hypersensitive  to  cold,  can  be  desensitized  by  the 
simple  expedient  of  immersing  one  hand  in  cold  water  at  a  temperature  of 
50°  F.  (10°  C),  for  one  or  two  minutes  twice  a  day  for  three  or  four  weeks^ 

Systemic  Applications  of  Cold.  —  These  have  been  tried  clinically  for 
patients  who  have  advanced  malignant  disease.  In  some  instances  local 
applications  of  cold  have  been  used  in  conjunction  with  the  general  cool- 
ing. Theorizing  that  increased  temperature  alone  is  required  to  bring 
into  existence  activation  of  the  rapid  embryological  cellular  division  in 
hen's  eggs,  that  in  plant  life  darkness  and  sustained  abnormally  high 
temperatures  give  rise  to  overgrowth  and  delayed  maturity,  and  that 
intense  sunlight  and  sustained  low  temperatures  tend  toward  a  slow  and 
stunted  maturity.  Fay  and  Henny^^  advocated  trials  of  "refrigeration" 
in  cases  of  carcinoma.  They  reported  five  cases  in  which  "responses" 
were  noted.  They  claimed  "definite  relief  of  local  pain"  and  "apparent 
gross  retardation  in  growth  as  well  as  diminution  in  the  size  of  the 
carcinomatous  lesions". 

Later  Smith  and  Fay^^,  expanding  on  the  hypothesis  that  carcinoma- 
tous metastatic  lesions  are  most  common  in  bodily  segments  in  which  the 
temperature  is  highest,  again  advocated  "refrigeration"  therapy.  They 
reported  that  local  application  of  cold  at  approximately  36°  F.  (2.2°  C.) 
to  the  pelvis  of  a  patient,  who  had  a  massive  pelvic  extension  of  a  carci- 
noma of  the  cervix,  caused  relief  from  pain  in  48  hours,  that  within  5 
days  there  was  devascularization  of  the  carcinomatous  region  with  shrink- 
age, and  within  3  weeks  there  was  evidence  of  repair  with  fibrous  tissue. 

Prolonged  intense  cold  applied  to  normal  tissues  could  be  expected  to 
produce  much  the  same  effects,  and  in  the  light  of  the  studies  of  Breedis 

Vol.  I.  941 


CONTRAINDICATIONS   TO   APPLICATIONS   OF   COLD     791 

and  his  associates'",  previously  mentioned,  the  temperatures  employed 
could  have  little  effect  on  the  malicjnant  cells.  In  normal  tissues  cold 
always  will  tend  to  produce  devascularization,  shrinkage  and  tissue 
damage  which,  of  course,  will  be  followed  by  repair  with  fibrous  tissue. 

Therefore,  the  hypotheses,  which  have  been  set  forth  by  Fay  and  his 
associates  as  bases  for  suggesting  this  form  of  therapy  in  cases  of  carci- 
noma, are  debatable.  The  number  of  cases  reported  to  date  is  so  limited 
that  the  whole  problem  remains  in  the  realm  of  pure  conjecture.  I  would 
not  give  the  question  so  much  attention  here,  were  it  not  for  the  fact 
that  much  publicity  regarding  this  work  has  swamped  me  with  numerous 
inquiries  concerning  it. 

Until  definite  proof  is  forthcoming,  it  seems  evident  that  no  clinician 
is  justified  in  employing  the  procedure  as  a  therapeutic  measure  in  carci- 
noma, unless  he  desires  to  do  so  from  an  experimental  angle  in  an  in- 
stitution properly  equipped  for  such  investigative  work. 

Systemic  applications  of  cold  have  been  suggested  in  treatment  for 
lymphatic  leukemia,  but  again  the  studies  of  Breedis  and  his  associates'" 
suggest  the  futility  of  the  method,  and  there  is  no  clinical  proof  of  its 
effectiveness.  Troedsson^  stated  that  mild  generalized  "hypothermy" 
might  be  found  useful  in  reducing  a  temporarily  high  fever,  a  high  meta- 
bolic rate  or  rapid  cardiac  action  "to  give  the  heart  a  rest".  At  present 
none  of  these  procedures  has  been  investigated  sufficiently  to  warrant  its 
general  use.  Currently  local  applications  of  cold  can  be  said  to  be  of 
clinical  value,  but  systemic  applications  of  cold  have  not  been  developed 
to  a  point  at  which  they  can  be  employed  in  clinical  practice. 

Contraindications  to  Applications  of  Cold 

Cold  should  not  be  employed  for  patients  who  have  a  definite  hyper- 
sensitivity to  it,  nor  should  it  be  applied  to  the  skin  in  the  presence  of 
cutaneous  atrophy,  radiodermatitis  or  melanotic  nevus.  It  has  been 
suggested^^  that  prolonged  cold  therapy  for  inflammations  may  lessen 
vitality  and  hinder  repair. 

The  danger  signs  noted  during  systemic  application  of  cold  include 
slowing  of  pulse  and  respiration  and  lowering  of  blood  pressure.  Although 
general  applications  of  cold  have  not  been  employed  sufficiently  for  one  to 
define  the  contraindications  clearly,  it  seems  obvious  that  the  procedure 
should  not  be  employed  in  asthenic  individuals  or  in  the  presence  of  any 
marked  circulatory  or  renal  disturbance.  Respiratory  infections  also 
would  seem  to  contraindicate  its  employment.  Acute  pancreatitis  has 
occurred  following  "refrigeration  therapy". 

Vol.  I.  941 


792  PHYSICAL   MEDICINE 

Summary  of  Data  on  Cold  Applications 

Local  or  general  applications  of  cold  will  cause  profound  physiological 
changes.  There  are  numerous  methods  of  applying  cold  therapeutically. 
There  are  several  indications  for  the  local  applications  of  cold.  Chief 
among  them  are  traumatic  lesions,  inflammations  and  congestions.  Gen- 
eral application  of  cold  is  still  in  the  experimental  stage  of  development, 
and  there  are,  at  present,  no  indications  for  its  clinical  employment. 

BIBLIOGRAPHY    OF    COLD    APPLICATIONS 

1.  HORTON,  B.  T.,  BROWN,  G.  E.  and  ROTH,  G.  M.:    Hypersensitiveness  to 

cold  with  local  and  systemic  manifestations  of  a  histamine-like  character; 
its  amenability  to  treatment,  Jour.  Am.  Med.  Assoc,  1936,  CVII,  1263. 

2.  BAZETT,  H.  C:   The  physiological  basis  for  the  use  of  heat,  Vol.  I,  pp.  1-29, 

in  Principles  and  Practice  of  Physical  Therapy,  Prior,  Hagerstown,  Mary- 
land, 1934,  Chapt.  I. 

3.  BROOKS,  B.  and  DUNCAN,  G.  W.:    The  effects  of  temperature  on  the  sur- 

vival of  anemic  tissue;  an  experimental  study,  Ann.  Surg.,  1940,  CXII,  130. 

4.  OPPENHEIMER,  M.  J.   and   McCRAVEY,  A.:    Circulation  time  in  man  at 

low  temperatures.  Am.  Jour.  Physiol.,  1940,  CXXIX,  434. 

5.  HARKINS,   H.   N.   and  HARMON,   P.   H.:    Experimental  freezing;    bleeding 

volume,  general  and  local  temperature  changes,  Proc.  Soc.  Exper.  Biol, 
and  Med.,  1935,  XXXII,  1142. 

6.  OPPENHEIMER,  M.  J.:    Personal  communication  to  the  author. 

7.  TROEDSSON,  B.  S. :    Experimental  lowering  of  body  temperature  of  rabbits 

and  its  possible  application  in  man,  Arch.  Phys.  Therapy,   1939,  XX,  501. 

8.  MEADER,  R.  G.  and  MARSHALL,  C:   Studies  on  the  electrical  potentials  of 

Hving  organisms:  II.  Effects  of  low  temperatures  on  normal  unanes- 
thetized  mice,  Yale  Jour.  Biol,  and  Med.,  1938,  X,  365. 

9.  HAINES,  R.  B.:   The  effect  of  freezing  on  bacteria,   Proc.  Roy.  Soc,  London, 

s.  B.,  1938,  CXXIY  451. 

10.  BREEDLS,  C,  BARNES,  W.  A.  and  FURTH,  J.:    Effect  of  rate  of  freezing 

on  the  transmitting  agent  of  neoplasms  of  mice,  Proc.  Soc.  Exper.  Biol, 
and  Med.,  1937,  XXXVI,  220. 

11.  FAY,  T.  and  HENNY,  G.  C:    Correlation  of  body  segmental  temperature  and 

its  relation  to  the  location  of  carcinomatous  metastasis;  clinical  observa- 
tions and  response  to  methods  of  refrigeration,  Surg.,  Gynec.  and  Obst., 
1938,  LXVI,  512. 

12.  SMITH,  L.  W.  and  FAY,  T.:    Temperature  factors  in  cancer  and  embryonal 

cell  growth.  Jour.  Am.  Med.  Assoc,  1939,  CXIII,  653. 

13.  BUNCH,   G.    H.:    Ischemic  necrosis  from  ice  bag   "burn",  Am.  Jour.  Surg., 

1936,  XXXII,  519. 
Sept.  I,  1941. 
Vol.  I.  941 


ULTRAVIOLET    RADIANT   ENERGY  793 


ULTRAVIOLET   RADIANT   ENERGY 

Ultraviolet  therapy  consists  of  treatment  by  means  of  radiation  from 
the  ultraviolet  portion  of  the  electromagnetic  spectrum  (Fig.  11).  Sun- 
light, particularly  during  the  summer  months,  is  a  more  or  less  satisfac- 
tory source  of  ultraviolet  radiation.  The  wavelengths  of  ultraviolet  rays 
vary  between  13.6  and  390  millimicrons. 

Ultraviolet  rays  with  wavelengths  between  13.6  and  290  millimicrons 
are  spoken  of  as  "far  ultraviolet  rays",  those  with  wavelengths  between 
290  and  390  millimicrons  as  "near  ultraviolet  rays".  Properly  employed 
ultraviolet  radiation  has  a  considerable  field  of  usefulness  in  medicine. 

Methods  of  Applying  Ultraviolet  Radiant  Energy 

There  are  several  sources  of  ultraviolet  energy  which  can  be  employed 
for  therapeutic  purposes.  These  include  the  sun,  various  types  of  quartz 
mercury  vapor  arcs  and  carbon  arcs.  To  select  a  source  of  ultraviolet 
radiation,  it  is  necessary  to  know  which  rays  the  source  produces,  their 
quantity  and  their  physiological  effects.  Different  ultraviolet  lamps  pro- 
duce different  amounts  of  radiation  from  various  regions  of  the  spectrum. 
Because  of  these  variations,  different  types  of  ultraviolet  lamps  may 
produce  distinctly  different  physiological  effects. 

It  is  apparent  that  the  user  of  such  a  lamp  must  know  the  rays  pro- 
duced and  their  effects.  Practically  all  sources  of  ultraviolet  radiation 
commonly  employed  produce  not  only  ultraviolet  rays  but  also  visible  and 
infra-red  rays. 

The  Sun.  —  Radiation  from  the  sun  has  its  spectral  limits  at  about 
290  millimicrons  in  the  ultraviolet  portion  of  the  electromagnetic  spectrum 
and  4,000  millimicrons  in  the  infra-red  portion.  The  greatest  intensity 
is  at  about  490  millimicrons.  The  sun  emits  very  little  ultraviolet  radia- 
tion of  wavelengths  shorter  than  350  millimicrons.  The  intensity  of  the 
rays  of  wavelengths  of  less  than  350  millimicrons  is  slight;  the  intensity 
then  increases  rapidly  to  490  millimicrons  and  above  that  decreases  grad- 
ually to  4,000  millimicrons  in  the  infra-red  region.  Sunlight  contains 
approximately  i  to  5  per  cent,  ultraviolet  radiation,  41  to  45  per  cent, 
visible  or  luminous  radiation  and  52  to  60  per  cent,  infra-red  radiation. 

The  sun  is  an  unreliable  source  of  ultraviolet  radiation  because  it  emits 
an  appreciable  amount  of  such  rays,  especially  during  winter,  only  for 
about  three  or  four  hours  in  the  middle  of  the  day.  The  intensity  of  ul- 
traviolet radiation   is  much  greater  at  high   altitudes  than  at  sea  level. 

Vol.  I.  941 


794 


PHYSICAL   MEDICINE 


Much  of  the  radiation  is  absorbed  by  water  vapor  at  the  lower  atmos- 
pheric levels. 

The  Quartz  Mercury  Vapor  Arc.  —  Radiation  from  the  quartz  mercury 
arc  lamp  consists  of  a  series  of  intense  spectral  lines,  namely,  at  257, 
265,  280,  297,  302,  313,  334  and  365  millimicrons,  superimposed  on  a 
faint  continuous  spectrum  extending  throughout  the  visible  and  into  the 
infra-red  region.     The  radiation  from  such  a  lamp  is  composed  of  approx- 


<* 

k 

& 

^^'                Tair^pi|^  . 

/i 

'    ■- 

^ 

Fig.   17.     A  quartz  mercury  vapor  arc  lamp. 


imately  6  per  cent,  far  ultraviolet  rays,  which  have  a  high  germicidal 
action,  and  which  are  completely  absent  in  sunlight,  28  per  cent,  total 
ultraviolet  rays,  20  per  cent,  luminous  rays  and  52  per  cent,  infra-red  rays. 

Quartz  tubes  containing  a  mercury  vapor  arc  usually  are  enclosed  in 
an  adjustable  reflector  and  applied  over  large  regions  of  the  body  for 
purposes  of  general  irradiation  (Fig.  17).  Smaller  quartz  tubes  contain- 
ing a  mercury  arc  sometimes  are  enclosed  in  a  water  jacket  to  cool  the 
burner  so  that  it  can  be  brought  close  to  the  skin.  These  water-cooled 
quartz  lamps  often  are  called  "Kromayer"  lamps. 

Vol.  I.  941 


ULTRAVIOLET    RADIANT   ENERGY 


795 


Fig.   i8.     A  new  type  of  air-cooled  Kromayer  lamp. 


Recently  an  air-cooled  Kromayer  lamp  (Fig.   i8)  has  been  developed 
for  local  irradiation;    this  is  rather  similar  to  the  old  water-cooled  units 
Vol.  I.  941 


796 


PHYSICAL   MEDICINE 


with  the  exception  that  the  small  burner  is  cooled  by  means  of  an  air 
blower  and  not  by  circulating  cold  water.  Quartz  rods  and  disks  can  be 
placed  over  the  window  of  this  lamp  for  the  purpose  of  conducting  the 
radiation  to  the  surface  or  to  the  orifice  which  is  to  be  exposed  (Fig.  19). 
The  Carbon  Arc.  —  Radiation  from  a  carbon  arc  lamp  varies  according 
to  the  kind  of  "carbon  pencils"  employed.  Electrodes  of  pure  carbon 
are  not  employed  therapeutically.  The  pencil-like  carbon  electrodes 
contain  a  core  composed  usually  of  metallic  salts.  By  varying  the  con- 
stituents of  these  cores  the  arc  can  be  altered  and  its  radiation  modified. 


Fig.   19.     Quartz  disks  and  rods,  which  are  employed  with  the  Kromayer  lamp  to 
conduct  the  radiation  into  bodily  orifices  or  to  small  local  regions  of  the  body. 


Carbons  which  contain  such  metallic  cores  are  spoken  of  as  "impregnated 
carbons". 

The  "A"  or  "sunshine^^  carbon.  The  type  of  carbon  most  commonly 
used  in  therapeutic  lamps  is  known  as  an  "A"  or  "sunshine"  carbon. 
It  is  impregnated  with  "rare  earth"  oxides,  and  its  arc  produces  radia- 
tion which  has  a  spectral  range  from  220  millimicrons  in  the  ultraviolet 
region  to  more  than  4,000  millimicrons  in  the  infra-red  region.  The 
spectrum,  which  it  produces,  approaches  that  of  sunlight  but  still  is  far 
from  being  an  exact  match.  Radiation  from  this  source  contains  5 
per  cent,  ultraviolet  rays,  50  per  cent,  luminous  rays  and  45  per  cent, 
infra-red  rays. 

Vol.  I.  941 


ULTRAVIOLET    RADIANT   ENERGY  797 

The  "5"  carbon.  The  "B"  carbon  is  similar,  but  it  is  impregnated 
with  iron  oxide,  and  its  spectrum  more  nearly  resembles  that  of  the  mer- 
cury arc.  This  carbon  is  particularly  rich  in  radiation  of  wavelengths 
shorter  than  310  millimicrons. 

The  "C"  carbon.  The  "C"  carbon  is  impregnated  with  calcium 
oxide  and  is  particularly  rich  in  radiation  in  the  region  between  290  and 
320  millimicrons.  Its  arc  emits  9  per  cent,  ultraviolet  rays,  24  per  cent, 
luminous  rays  and  67  per  cent,  infra-red  rays. 

The  "£"  carbon.  The  other  type  of  carbon,  which  commonly  is 
employed  therapeutically,  is  known  as  the  "E"  carbon.  The  radiation, 
which  is  emitted  by  its  arc,  is  similar  to  that  produced  by  a  tungsten 
filament  lamp;  it  is,  therefore,  a  good  source  of  near  infra-red  rays.  The 
radiation  is  particularly  rich  in  rays  from  the  spectral  region  between 
550  and  750  millimicrons  in  the  orange  and  red  portions  of  the  visible 
spectrum.     It  emits  much  radiation  in  the  near  infra-red  region. 

Usually  therapeutic  carbon  arc  lamps  consist  of  two  carbons  arranged 
end  to  end  in  a  suitable  reflector  (Fig.  20).  The  carbons  are  connected 
to  a  source  of  electricity.  When  they  are  brought  together  momentarily, 
the  electrical  circuit  is  completed,  and  then  when  they  are  separated 
slightly,  an  intense  electrical  arc  forms  between  the  tips  of  the  carbon 
electrodes.  The  carbon  electrodes  are  consumed  gradually  and  must  be 
replaced  from  time  to  time. 

The  chief  advantage  of  the  carbon  arc  lamp  is  that  the  carbons  can 
be  changed  to  vary  the  radiation  produced.  Thus  different  therapeutic 
effects  can  be  achieved  with  the  same  lamp. 

The  ''Cold  Quartz''  Lamp.  —  In  the  past  few  years  an  ultraviolet 
lamp,  which  is  practically  devoid  of  heat,  has  been  marketed.  It,  there- 
fore, has  been  called  a  "cold  quartz"  lamp.  It  consists  of  quartz  tubing 
containing  neon  and  mercury  vapor  through  which  is  passed  an  electric 
charge  of  high  voltage.  The  appearance  of  the  tubing  is  similar  to  that  of 
the  familiar  neon  signs  commonly  used  in  advertising.  This  tubing  usually 
is  shaped  into  a  serpentine  grid  which  is  placed  over  the  face  of  a  reflector. 

The  radiation  from  this  lamp  consists  of  one  very  intense  spectral 
line  at  254  millimicrons  and  a  series  of  a  few  much  less  intense  lines.  The 
lines  at  297  and  313  millimicrons  are  fairly  intense,  but  95  per  cent,  "of 
the  total  radiation  of  wavelengths  less  than,  and  including,  313  millimi- 
crons is  contained  in  the  resonance  emission  line  at  254  millimicrons". 
Because  of  its  limited  range  of  radiation  this  type  of  lamp  has  a  limited 
field  of  usefulness. 

Sun  Lamps.  —  In  the  past  few  years  several  kinds  of  sun  lamps  have 
been  constructed  for  home  use.     Typical  of  this  group  of  lamps  is  the 

Vol.  I.  941 


798 


PHYSICAL   MEDICINE 


Fig.  20.     A  carbon  arc  lamp  of  the  type  commonly  employed  in  a  physician's  office. 
Vol.  I.  941 


PRINCIPLES   OF   ULTRAVIOLET    RADIANT   ENERGY      799 

"S-i"  lamp.  It  consists  of  a  tungsten  filament,  two  tungsten  electrodes 
and  a  drop  of  mercury  enclosed  in  a  bulb  of  ultraviolet  transmitting  glass. 
When  it  is  turned  on,  the  filament  becomes  hot,  and  the  mercury  vaporizes 
and  forms  a  mercury  vapor  arc  between  the  electrodes.  This  arc  emits 
ultraviolet  rays  (Fig.  21).     The  radiation  is  not  unlike  that  of  the  other 


Fig.  21.  An  S-i  lamp,  which  is  a  suitable  source  of  ultraviolet  radiation  for  use  in 
the  home  (From  Krusen,  F.  H.:    Physical  Medicine,  Saunders,  Philadelphia,  1941). 

hot  mercury  quartz  lamps.  It  emits  5  per  cent,  ultraviolet  rays,  78  per 
cent,  luminous  rays  and  17  per  cent,  infra-red  rays.  At  a  distance  of  2 
feet,  60  cm.,  its  output  of  ultraviolet  rays  is  about  equivalent  to  that  of 
noontime  sunlight  in  June. 

Other  similar  sun  lamps,  which  recently  have  been  approved  as  suit- 
able devices  by  the  Council  on  Physical  Therapy  of  the  American  Medical 
Association,  are  the  "S-4"  lamp  and  the  "L.  M.-4"  lamp.  Still  another 
suitable  sun  lamp,  which  produces  radiation  similar  to  that  of  the  "S-i" 
lamp,  is  the  "type  G  mercury  glow  lamp".  These  lamps  will  not  be 
described  in  detail. 


Physical  Principles  Concerned  in  the  Application 
OF  Ultraviolet  Radiant  Energy 

The  electromagnetic  spectrum  already  has  been  mentioned  briefly. 
The  physician,  who  uses  ultraviolet  radiation  therapeutically,  must  be 
familiar  with  the  properties  and  the  efTects  of  the  rays  derived  from  var- 
ious portions  of  this  spectrum,  if  he  is  to  use  his  lamp  intelligently. 

The  unit  of  measurement  of  wavelength  of  radiation,  which  is  em- 
ployed commonly  by  the  United  States  Bureau  of  Standards,  is  the  milli- 

VoL.  I.  941 


8oo  PHYSICAL   MEDICINE 

micron,  usually  abbreviated  m/x.  The  other  unit  of  measurement  of 
wavelength,  which  sometimes  is  employed,  is  the  Angstrom  unit,  usually 
abbreviated  A.  U.  or  A.°.  An  Angstrom  unit  is  o.i  millimicron  (Table 
I).  The  electromagnetic  spectrum  is  represented  in  graphic  form  in 
Fig.  II  and  in  tabular  form  in  Table  II. 

The  ultraviolet  rays  with  wavelengths  ranging  between  13.6  and  390 
millimicrons  possess  varying  physical  properties  and  produce  a  variety  of 
effects  which  are  chiefly  of  a  chemical  nature.  For  example,  there  is  a 
band  of  ultraviolet  rays  between  290  and  315  millimicrons,  sometimes 
called  the  "vital  ultraviolet  band",  which  possesses  antirachitic  properties, 
and  which  converts  more  than  60  per  cent,  of  the  provitamin,  ergosterol 
or  7-dehydrocholesterol,  into  vitamin  D.  On  the  other  hand  the  group 
of  ultraviolet  rays,  the  wavelength  of  which  is  shorter  than  280  milli- 
microns, are  chiefly  bactericidal  and  abiotic,  capable  of  destroying  tis- 
sue cells,  and  tend  to  destroy  vitamin  D. 

It  is  apparent  that,  to  obtain  the  maximal  antirachitic  effect  from  a 
source  of  ultraviolet  radiation,  the  lamp  used  should  produce  little  or 
none  of  the  rays  of  wavelength  shorter  than  290  millimicrons  and  should 
be  rich  in  radiation  from  the  "vital  ultraviolet  band".  Similarly,  if  a 
maximal  bactericidal  effect  is  desired,  a  source  rich  in  the  ultraviolet 
rays  of  shorter  wavelength  should  be  employed. 

Penetration  of  ultraviolet  rays  through  the  skin  or  through  mucous 
membranes  never  exceeds  a  depth  of  2  mm.  Various  substances  not  only 
absorb  such  radiation  but  also  reflect  some  of  the  rays.  The  most  ab- 
sorbent substance  will  reflect  some  of  the  rays,  and  conversely  the  most 
efficient  reflector  will  absorb  some  of  the  radiation.  The  amount  of 
absorption  by  human  tissues  depends  largely  on  the  wavelength  of  the 
radiation  and  the  output  of  energy  from  the  source. 

Action  and  Uses  of  Ultraviolet  Radiant  Energy 

Exposure  to  ultraviolet  rays  produces^  photochemical  effects  with 
activation  of  certain  substances  in  the  skin  and  also  possibly  in  the 
blood.  Also  certain  biological  effects  have  been  observed  such  as  stimula- 
tion of  metabolism  and  growth  and  increase  of  circulation  and  cellular 
activity. 

Ultraviolet  rays  of  wavelengths  between  290  and  315  millimicrons  have 
the  specific  property  of  preventing  and  curing  rickets.  Radiation  from 
this  same  "vital"  region  possesses  the  ability  to  impart  an  antirachitic 
potency  to  fats,  milk,  ergosterol,  7-dehydrocholesterol  (the  sterol,  found  in 
human  skin,  which  can  be  activated),  oils  and  vegetables.     If  pregnant  or 

Vol.  I.  941 


ACTION  AND   USES  OF   RADIANT  ENERGY  8oi 


TABLE  I 
Units  of  Measurement  of  Wavelengths 


One  angstrom  unit 
(A.  U.  or  A.°) 

One-tenth  millimicron  or  one- 
ten-millionth  millimeter 

One-millimicron  (m^) 

Ten  angstrom  units  or  one- 
millionth  millimeter 

One  micron  (m) 

One-thousandth  millimeter 

One  millimeter  (mm.) 

One-tenth  centimeter  or  one- 
thousandth  meter 

TABLE  II 
Electromagnetic  Spectrum 


Rays 


Gamma  rays 


Extent  of  wavelengths 


Roentgen  rays 


Ultraviolet  rays 


Visible  rays 


far 


violet 


blue 


green 


yellow 


0.00 1  to 


0.14     niju 


0.14    to  13.6       m^ 


13.6      to  290.         m/n 


290.        to  390.         mju 


390.        to  450.         mM 


450.        to  490.         m/x 


490.        to  550.         m^ 


Infra-red  rays 


orange 


red 


near 


far 


Hertzian  waves 


550.        to  590.         mM 


590.        to  630. 


m(u 


630.        to  770. 


mM 


770.         to       1,400.  niM 


1,400.         to     15,000. 


mM 


15,000.  mM  to  several  kilometers 


nursing  mothers   or  cows   are   exposed  to  these  rays,  their  milk  will  de- 
velop an  antirachitic  potency.  .       ,        ,  • 
Ultraviolet  rays  will  cause  a  delayed  or  latent  erythema  m  the  skm 

Vol.  I.  941 


802  PHYSICAL   MEDICINE 

of  human  beings.  Repeated  exposures  to  erythemal  doses  lead  to  the 
production  of  diffuse  pigmentation  of  the  skin  of  the  white  man.  Such 
pigmentation  probably  assists  in  the  absorption  of  radiant  energy  which 
is  transformed  into  heat. 

There  is  evidence  to  indicate  that  ultraviolet  irradiation  of  the  human 
being  causes  improvement  of  the  tone,  color  and  elasticity  of  the  skin  and 
presumably  also  increases  the  secretory  and  protective  powers  of  the  skin. 
Exposures  of  large  portions  of  the  cutaneous  surface  to  ultraviolet  ra- 
diation produces  activation  of  a  constituent  of  the  cutaneous  cholesterol, 
7-dehydrocholesterol,  to  form  vitamin  D,  which  in  turn  stimulates  ab- 
sorption of  calcium  and  phosphorus  from  the  intestinal  tract  and  increases 
metabolic  efficiency.     Phytosterol  of  plants  is  activated  similarly. 

It  has  been  reported  that  ultraviolet  irradiation  causes  an  increase 
of  the  active  oxygen  content  of  the  lipids  of  the  skin  and  consequently  an 
increase  in  their  bactericidal  action.  It  is  possible  also  that  exposure  to 
ultraviolet  rays  leads  to  the  formation  of  hormones  in  the  skin  and  accom- 
plishes the  activation  of  useful  cutaneous  reflexes. 

On  general  exposure  to  ultraviolet  radiation  the  number  of  erythro- 
cytes, leukocytes,  blood  platelets  and  hemoglobin  of  the  circulating  blood 
may  increase  slightly,  and  the  hydrogen  ion  concentration,  coagulation 
time  and  eventually  the  volume  of  blood  may  decrease.  In  general  dark- 
ness produces  a  reverse  effect  with  the  exception  that  the  blood  volume 
seems  to  be  diminished.  Exposure  to  ultraviolet  rays  produces  an  in- 
crease in  serum  globulin.  Ultraviolet  irradiation  is  believed  to  cause  a 
possible  increase  in  bodily  resistance  by  increasing  the  bactericidal  power 
of  the  blood  which  depends  largely  on  the  leukocytic  reaction.  Such 
radiation  probably  does  not  influence  specific  immunity. 

In  moderate  doses  ultraviolet  radiation  causes  an  increase  in  carbon 
dioxide  tension  and  a  relative  alkalosis,  while  in  heavy  doses  it  produces  a 
decreased  carbon  dioxide  tension  and  acidosis.  It  has  been  demonstrated 
that  ultraviolet  irradiation  causes  a  lessening  of  the  toxicity  of  the  serum 
of  the  patient  who  has  pernicious  anemia. 

General  ultraviolet  irradiation  produces  a  transient  lowering  of  blood 
pressure.  The  factors,  which  probably  are  responsible  for  the  reduction 
of  blood  pressure,  are  the  production  of  cutaneous  hyperemia,  the 
decrease  in  the  viscosity  of  the  blood,  the  development  of  cutaneous  de- 
pressor substances  and  the  production  of  sympathetic  hypotonia.  Activa- 
tion of  the  circulation  has  been  attributed  to  the  vasodilating  effect  of 
the  ultraviolet  erythema  and  its  continuous  tonic  action  on  the  nerve 
endings.  It  has  been  shown  also  that  these  rays  cause  increased  per- 
meability of  cell  membranes  and  capillaries. 

Vol.  I.  941 


ACTION   AND   USES  OF    RADIANT   ENERGY  803 

In  general  ultraviolet  rays  of  wavelengths  longer  than  290  millimicrons 
produce  presumably  stimulative  effects  on  the  human  body,  but  if  the 
rays  are  of  wavelengths  shorter  than  290  millimicrons  and  in  large  quan- 
tities, they  will  have  a  lethal  effect  on  the  cells  of  the  human  body.  In 
smaller  quantities  the  rays  of  shorter  wavelength  may  have  a  stimulative 
action  on  the  cells.  These  effects  are  due,  perhaps,  to  the  production  of 
a  toxic  photo-product,  which  in  large  quantities  is  lethal  and  in  small 
quantities  acts  as  a  stimulant  to  cell  division. 

Other  general  effects  of  ultraviolet  irradiation  have  been  noted;  these 
include  improvement  of  muscular  tone,  increase  in  protein  and  mineral 
metabolism,  possible  lowering  of  sympathetic  tone,  possible  stimulation 
of  intracellular  oxidation  and  possible  increase  in  the  rate  of  bodily  growth. 

The  application  of  ultraviolet  rays  does  not  act  as  a  substitute  for 
dietary  deficiencies  but  produces  an  increase  in  the  ability  of  the  organism 
to  utilize  more  effectively  materials  which  are  present  but  are  not  other- 
wise available.  It  is  said  that  general  exposure  to  ultraviolet  rays  causes  a 
decrease  in  the  rate,  but  an  increase  in  the  depth,  of  respiration. 

Finally  ultraviolet  radiation  has  a  definite  bactericidal  action.  The 
line  at  266  millimicrons  is  the  most  highly  bactericidal;  it  is  followed  in 
order  of  effectiveness  by  the  lines  at  254,  280,  248  and  270  millimicrons. 
It  has  been  demonstrated  recently  that  the  very  short  rays  with  wave- 
lengths of  less  than  240  millimicrons  have  some  germicidal  action. 
Stimulation  of  bacterial  growth  has  not  been  observed  to  result  from  ex- 
posure to  ultraviolet  rays. 

The  use  of  ultraviolet  radiation  in  the  treatment  of  disease  has  been 
most  extensive,  but  much  of  the  literature  on  the  subject  has  been  written 
poorly  and  is  of  an  unconvincing  nature.  It  is  essential,  therefore,  that 
physicians  make  a  careful  analysis  of  the  writings  on  this  subject  and 
accept  only  those  which  seem  to  have  proved  their  claims  by  properly 
controlled  studies'-. 

Diseases  of  the  Alimentary  Tract.  —  There  is  now  sufficient  evidence 
to  indicate  that  ultraviolet  irradiation  may  be  of  distinct  value  in  the 
treatment  of  tuberculous  peritonitis  and  enteritis.  Since  intestinal  tubercu- 
losis is  one  of  the  most  frequent  complications  of  pulmonary  tuberculosis, 
occurring  as  it  does  in  from  50  to  80  per  cent,  of  all  fatal  cases,  any 
measure  that  will  be  of  benefit  is  of  the  utmost  importance.  Ultraviolet 
irradiation  is  one  of  the  most  important  factors  in  the  arrest  and  treat- 
ment of  intestinal  tuberculosis.  In  a  survey  of  the  records  of  8,087  rou- 
tine postmortem  examinations  evidence  of  pulmonary  tuberculosis  was 
found  in  886  cases  and  of  intestinal  tuberculosis  in  233  cases.  The  ratio 
of    pulmonary    to    intestinal    tuberculosis    was,    therefore,    approximately 

Vol.  I.  941 


8o4  PHYSICAL   MEDICINE 

4:1.  Of  180  patients,  who  had  intestinal  tuberculosis  and  had  received 
treatment  at  Saranac  Lake,  65  per  cent,  of  those  treated  with  ultraviolet 
light  were  alive,  whereas  of  those  not  so  treated  only  17  per  cent,  were 
alive  at  the  time  of  the  report.  At  the  Trudeau  Sanatorium  of  a  series 
of  106  patients,  who  had  intestinal  tuberculosis,  88  per  cent,  of  those 
treated  by  ultraviolet  light  survived,  whereas  only  25  per  cent,  of  those 
not  so  treated  survived. 

Following  the  use  of  the  mercury  quartz  lamp  in  the  treatment  of  in- 
testinal tuberculosis,  tubercle  bacilli  often  disappear  from  the  stools; 
pain,  nausea  and  vomiting  are  relieved,  but  the  diarrhea  and  intestinal 
disturbances  tend  to  resist  the  longest.  In  the  treatment  of  tuberculous 
peritonitis  the  best  results  are  obtained  in  the  ascitic  type.  In  abdominal 
tuberculous  adenitis  it  may  be  unwise  to  temporize  with  light  therapy, 
since  in  more  than  three-fourths  of  the  cases  it  is  possible  to  excise  the 
affected  glands. 

Ultraviolet  irradiation  has  been  recommended  in  the  treatment  of 
pylorospasm.  It  is  possible  that,  when  this  condition,  as  seems  often  the 
case,  is  associated  with  calcium  deficiency,  ultraviolet  irradiation  may  be 
of  value. 

Diseases  of  the  Blood  and  Circulatory  System.  —  In  the  treatment  of  sec- 
ondary anemia  it  has  been  suggested  that  one  of  the  important  factors 
in  an  ideal  program  consists  of  adequate  exposure  to  ultraviolet  radiation. 
There  is  considerable  similarity  between  anemia  and  rickets,  a  disease 
cured  and  prevented  by  ultraviolet  irradiation,  when  there  is  an  adequate 
intake  of  calcium  and  phosphorus.  In  both  diseases  there  is  lowered 
gastrointestinal  acidity,  pH,  which  interferes  with  the  absorption  of  cal- 
cium and  with  the  absorption  of  iron,  with  a  resultant  decrease  in  the 
amount  of  iron  available  for  regeneration  of  blood.  In  both  diseases 
changes  in  the  bone  marrow  and  modifications  in  the  types  of  cells  may 
be  seen.  Ultraviolet  irradiation  may  be  beneficial  in  the  treatment  of 
either  disease. 

In  a  study  conducted  for  a  period  of  more  than  eight  years  in  an  arti- 
ficial light  clinic  for  school  children  it  was  found  that  after  twelve  or  more 
exposures  to  irradiation  from  a  carbon  arc  lamp  the  amount  of  hemo- 
globin of  anemic  children  increased  by  approximately  10  per  cent.  An- 
other controlled  study  of  the  use  of  ultraviolet  irradiation  in  54  cases  of 
secondary  anemia  indicated  greater  increases  in  hemoglobin  and  in  the 
number  of  erythrocytes  and  leukocytes  in  the  treated  than  in  the  control 
group.  It  has  been  suggested  that  further  studies  of  patients,  who  have 
secondary  anemia,  may  indicate  a  possible  influence  of  ultraviolet  irradia- 
tion on  the  chemical  constituents  of  the  blood.     Although  various  studies 

Vol.  I.  941 


ACTION   AND   USES  OF   RADIANT   ENERGY  805 

indicate  that  ultraviolet  radiation  may  be  a  useful  adjunct  in  the  treat- 
ment of  secondary  anemia,  there  are  still  insufficient  data  to  indicate  the 
exact  value  of  this  therapeutic  measure. 

Various  observers  have  shown  that  ultraviolet  irradiation  does  pro- 
duce transient  reduction  in  blood  pressure.  The  work  of  Laurens^  and  his 
coworkers  in  this  field  has  been  most  convincing.  As  a  therapeutic 
measure,  however,  it  is  doubtful  whether  ultraviolet  irradiation  can  be 
considered  more  than  a  slight  adjunct  to  the  treatment  of  hypertension. 

Ultraviolet  irradiation  has  been  employed  for  carbon  monoxide  poison- 
ing because  Haldane  and  Hartridge  showed  that  the  dissociation  of  carbon 
monoxide  and  hemoglobin  was  increased  markedly  under  the  influence 
of  ultraviolet  light.     Such  treatment  has  been  found  to  be  beneficial. 

Diseases  of  the  Respiratory  System.  —  Many  articles  have  been  prepared, 
pro  and  con,  with  regard  to  the  use  of  general  ultraviolet  irradiation  in 
the  prevention  and  treatment  of  the  common  cold.  At  Cornell  University* 
small  groups  of  male  students  were  irradiated  with  minimal  erythema 
doses  of  ultraviolet  rays  once  weekly  during  the  winter  months.  There 
was  an  apparent  reduction  in  the  incidence  of  colds  ranging  from  27.9  to 
55.5  per  cent.  At  Vanderbilt  University^  an  investigation  on  the  manage- 
ment of  common  colds  revealed  decided  improvement  in  cases  in  which 
ultraviolet  irradiation  was  used. 

At  the  Cook  County  Hospital"  ultraviolet  irradiation  was  recommended 
in  the  treatment  of  chronic  coughs.  It  was  said  to  have  a  stimulating 
effect  on  general  metabolism  and  on  resistance  to  infection,  provided  the 
optimal  dose  was  not  exceeded  and  the  patient  was  free  from  fever. 

On  the  other  hand  some  investigators  have  been  of  a  contrary  opinion; 
thus  it  has  been  concluded  that,  although  the  mercury  quartz  lamp  has 
been  used  extensively  to  enhance  individual  resistance  to  colds,  well- 
controlled  studies  on  both  infants  and  adults  nevertheless  have  failed  to 
corroborate  claims  for  its  value.  Hill  and  Clark^  found  little  to  support 
the  view  that  ultraviolet  irradiation  was  capable  of  increasing  a  person's 
natural  resistance.  Other  investigators  have  performed  experiments  simi- 
lar to  those  conducted  at  Cornell  with  results,  which  were  for  the  most 
part  negative,  although  they  did  find  that  in  certain  tests  the  resistance 
of  the  irradiated  group  was  greater  than  that  of  the  control  group.  Still 
other  investigators  observed  363  adults  for  thirty-five  weeks;  during  the 
first  thirty-one  weeks  approximately  half  the  group  were  given  frequent 
ultraviolet  irradiations,  a  single  minimal  erythema  dose  being  applied 
either  to  the  chest  or  to  the  back  at  each  treatment.  The  incidence  of 
colds  during  the  period  of  study  was  slightly  higher  in  the  irradiated  group 
than  in  the  control  group.     However,  it  should  be  pointed  out  that  failure 

Vol.  I.  941 


8o6  PHYSICAL   MEDICINE 

to  benefit  from  treatment  may  have  been  due  to  inadequate  dosage.  Only 
a  quarter  of  the  body  was  treated  at  any  session,  and  the  dose  was  not 
increased  at  subsequent  sessions.  It  is  agreed  generally  that  to  produce 
beneficial  systemic  effects  a  series  of  irradiations  to  the  entire  body  should 
be  given  and  that  the  dose  should  be  increased  gradually. 

Further  investigations  will  be  necessary  before  final  conclusions  can 
be  drawn  concerning  the  value  of  ultraviolet  irradiation  in  treating  com- 
mon colds. 

In  the  treatment  of  pulmonary  tuberculosis  there  likewise  has  been 
much  controversy  concerning  the  use  of  ultraviolet  irradiation.  Although 
ultraviolet  light  frequently  is  used  in  Europe  for  the  treatment  of  pul- 
monary tuberculosis,  in  this  country  it  often  has  been  thought  to  be 
dangerous.  It  has  been  stressed  especially  that  there  is  danger  of  pro- 
ducing pulmonary  hemorrhage.  My  own  controlled  studies^  on  60 
patients,  who  were  receiving  routine  sanatorium  care,  indicated  that  he- 
moptysis did  not  contraindicate  the  judicious  employment  of  heliother- 
apy, and  a  number  of  other  investigators  have  reached  similar  conclusions 
following  controlled  studies.  It  has  been  said  that  treatment,  which 
brings  about  improvement  in  the  general  health  of  the  patient,  is  the 
best  means  of  combating  pulmonary,  as  well  as  surgical,  tuberculosis. 

Observations  on  115  patients  treated  by  carbon  arc  irradiation  led  to 
the  conclusion  that  minimal,  moderately  advanced  or  even  far  advanced 
pulmonary  tuberculosis  may  be  benefited  by  graduated  irradiation,  if  the 
patient's  temperature  does  not  rise  above  37.5°  C.  (99.5°  F.)  and  his 
general  physical  condition  is  satisfactory.  In  Denmark  treatment  of 
pulmonary  tuberculosis  with  light  now  is  almost  universal,  and  in  Britain 
detailed  results  in  a  series  of  123  cases  led  to  the  conclusion  that,  if 
patients  are  selected  carefully,  chronic  pulmonary  tuberculosis  may  be 
treated  not  only  with  safety  but  with  good  results. 

Recently  a  number  of  writers  in  the  United  States  have  expressed  a 
similar  opinion.  It  has  been  reported  that  clinical  experience  will  con- 
vince one  of  the  value  of  the  mercury  quartz  vapor  lamp  in  the  treat- 
ment of  pulmonary  tuberculosis  of  children.  Tuberculous  infants,  who 
have  excessive  pulmonary  infiltration,  even  with  cavity  formation,  may 
recover. 

Although  I  believe  that,  judiciously  employed  in  conjunction  with 
routine  institutional  care,  light  therapy  may  be  of  value  as  an  adjunct 
in  the  treatment  of  pulmonary  tuberculosis,  its  indiscriminate  use  is 
fraught  with  danger.  Of  71  competent  observers  47  obtained  favorable 
and  24  either  poor  or  no  results  following  the  use  of  ultraviolet  irradia- 
tion   in    the    treatment    of    pulmonary    tuberculosis.      This    indicates    an 

Vol.  I.  941 


ACTION   AND   USES   OF    RADIANT   ENERGY  807 

almost  2:1  preponderance  in  favor  of  the  judicious  application  of  ultra- 
violet radiation.  For  far  advanced  toxic  or  advancing  active,  exudative 
pulmonary  tuberculosis  light  therapy  should  not  be  employed,  but  in- 
cipient pulmonary  tuberculosis,  especially  of  children,  and  nontoxic  lesions, 
which  have  reached  the  stage  of  chronicity,  may  be  benefited  by  the  care- 
ful administration  of  small  doses  of  general  ultraviolet  radiation.  Abun- 
dant rest,  an  increased  intake  of  food  and  proper  hygienic  measures  are 
more  important  in  the  treatment  of  tuberculosis  than  is  ultraviolet  ther- 
apy, which  is  merely  an  adjunct  to  these  other  measures. 

Diseases  of  the  Bones  and  Joints.  —  In  a  study  of  22  children,  who  had 
tuberculosis  of  the  bones  or  joints  and  were  treated  throughout  the  winter 
and  spring  with  radiations  from  a  carbon  arc  light  of  high  intensity,  it 
was  found  that  the  majority  showed  a  rise  in  the  blood  count,  a  tendency 
to  gain  weight  and  likewise,  a  marked  improvement  in  the  local  tubercu- 
lous lesions. 

An  extensive  study  on  the  nonoperative  treatment  of  tuberculous  joints 
of  the  lower  extremities  revealed  that,  over  a  period  of  years,  65  per  cent, 
of  the  adult  patients  under  treatment  for  all  extrapulmonary  tuberculous 
lesions  had  definite,  though  usually  inactive,  pulmonary  tuberculosis. 
Conservative  treatment  by  heliotherapy  in  conjunction  with  routine  care 
was  used  in  this  large  series  of  cases.  Of  437  patients  with  tuberculosis  of 
the  bones  and  joints  and  72  with  nontuberculous  osteomyelitis,  who  re- 
mained on  an  institutional  regimen  for  three  months  or  longer,  the  follow- 
ing conditions  were  revealed  on  dismissal:  53.8  per  cent,  apparently  had 
recovered;  the  tuberculosis  of  23.1  per  cent,  was  arrested;  10.7  per  cent, 
were  improved;  7.8  per  cent,  were  unimproved,  and  4.5  per  cent,  had 
died.  A  follow-up  of  these  patients  revealed  that  between  80  and  87 
per  cent,  were  working,  an  additional  8  to  10  per  cent,  were  ambulant 
but  unable  to  work,  and  between  3  and  5  per  cent,  were  confined  to  bed. 
It  was  concluded  that  such  conservative  treatment  usually  resulted  in 
healing  with  useful  motion.  Operative  interference  should  not  be  at- 
tempted until  after  prolonged  heliotherapy  has  been  tried. 

Bernhard'^,  as  a  result  of  twenty-five  years'  experience,  was  of  the 
opinion  that  in  the  treatment  of  surgical  tuberculosis  heliotherapy  was  the 
method  of  choice.  In  his  first  1,000  cases  of  surgical  tuberculosis  in  which 
heliotherapy  was  employed,  858  patients  were  cured,  120  were  improved, 
14  were  unimproved  and  8  had  died,  a  mortality  rate  of  only  0.8  per  cent. 
Six  of  the  patients,  who  were  unimproved,  died  later,  raising  the  final 
mortality  to  14  or  1.4  per  cent.  The  effect  of  heliotherapy' in  one  case 
is  shown  in  Fig.  22. 

Osteomalacia,  fragilitas  osseum  and  delayed  union  of  fractures  are  con- 

VoL.  I.  941 


8o8  PHYSICAL   MEDICINE 

ditions  which  may  be  due  to  faulty  calcium  metabolism,  and  ultraviolet 
irradiation  may  be  of  value.  In  a  study  of  experimental  fractures  of  the 
fibula  in  25  normal  dogs  and  80  normal  rats  measured  amounts  of  carbon 
arc   radiation  were  administered  during   the   period   of  healing.      During 


Fig.  22.  Patient  with  extrapulmonary  tuberculosis;  (a)  before  heliotherapy,  in 
April,  1927;  (b)  after  heliotherapy,  in  December,  1927  (Courtesy  of  Dr.  Richard  T. 
Ellison;    from  Krusen,  F.  H.:    Light  Therapy,  Ed.  2,  Hoeber,  New  York,  1937). 

this  period  73.9  per  cent,  of  the  fibulas  of  animals  irradiated  with  "sun- 
shine" carbons,  26.9  per  cent,  of  those  irradiated  with  "C"  carbons  and 
41.3  per  cent,  of  those  of  the  controls  healed.  The  average  healing  time 
for  fractures  was  3.7  days  shorter  when  the  animals  were  irradiated  than 
when  they  were  not.  In  fractures  of  the  long  bones  it  has  been  reported 
that  among  patients,  who  were  given  irradiated  ergosterol,  the  density 
Vol.  I.  941 


ACTION   AND   USES  OF   RADIANT   ENERGY  809 

and  the  amount  of  callus  increased  as  compared  with  a  control  group  of 
patients.  These  changes  were  greatest  in  children  and  in  the  aged,  and 
they  began  to  appear  about  three  weeks  following  injury.  On  the  other 
hand,  in  rabbits  and  rats,  given  respectively  3  and  1.25  gm.  of  irradiated 
ergosterol  by  mouth,  the  rate  of  healing  or  amount  of  callus  in  fractures 
of  the  tibia  and  fibula  did  not  increase. 

In  rats,  on  which  parathyroidectomy  has  been  performed  with  con- 
sequent parathyroid  deficiency,  calcification  does  not  occur  regularly  in 
the  callus  following  fracture,  if  calcium  is  lacking  also  in  the  diet;  under 
such  conditions  administration  of  irradiated  ergosterol  promotes  calcifica- 
tion of  callus. 

It  seems  logical  to  presume  that  ultraviolet  irradiation  has  little  in- 
fluence on  healthy  individuals,  whose  calcium  metabolism  is  normal,  but 
it  would  seem  that  it  might  be  of  value  for  patients  with  faulty  calcium 
metabolism,  who  sustained  fractures. 

A  number  of  authors  have  recommended  the  use  of  ultraviolet  radia- 
tion for  both  atrophic  and  hypertrophic  arthritis.  Although  there  is  no 
specific  effect,  it  is  believed  by  many  clinicians  that  ultraviolet  irradiation 
is  of  value,  particularly  when  there  is  an  associated  secondary  anemia,  or 
when  the  patient  has  been  confined  to  bed  for  a  long  period. 

It  has  been  claimed  that  ultraviolet  irradiation  tends  to  counteract 
the  decalcifying  process  in  the  bones  and  to  have  an  accessory  nutritional 
influence  in  managing  the  anemia,  debility  and  allied  conditions  so  fre- 
quently found  in  chronic  infectious  arthritis.  It  has  been  pointed  out, 
however,  that  chronic  infectious  arthritis  can  continue  as  a  progressive 
crippling  disease  even  in  the  Arizona  desert  unless  therapeutic  measures 
other  than  sunlight  and  climate  are  utilized. 

It  has  been  recommended  that  for  chronic  infectious  arthritis  of 
children  reasonable  exposure  to  sunlight  or  to  quartz  lights  be  utilized 
during  the  winter  months.  Ultraviolet  irradiation  has  been  recommended 
especially  in  the  treatment  of  psoriatic  arthritis.  A  combination  of  crude, 
coal  tar  ointment  and  ultraviolet  irradiations  is  applied  to  the  psoriatic 
lesions,  and  heat,  massage  and  exercise  are  applied  locally  to  the  involved 
joints  (see  also  treatment  of  psoriasis  in  the  latter  part  of  this  section 
under  the  subheading.  Diseases  of  the  Skin). 

Diseases  of  the  Genito-urinary  Syste?n.  ^  In  a  series  of  26  cases  follow- 
ing nephrectomy  for  renal  tuberculosis  ultraviolet  irradiation  proved  to  be 
a  most  helpful  therapeutic  measure  for  the  cure  of  the  tuberculous  sinuses 
and  visceral  ulceration  incident  to  the  disease.  It  has  been  said  likewise 
that  in  tuberculosis  of  the  genito-urinary  tract  surgical  treatment  fre- 
quently offers  prompt  relief  if  combined  with  postoperative  heliotherapy. 

Vol.  I.  941 


8io  PHYSICAL   MEDICINE 

Direct  irradiation  of  the  bladder  for  the  treatment  of  tuberculous  ulcer- 
ation or  cystitis  has  been  recommended  by  a  number  of  observers. 

Diseases  of  the  Eye.  —  Following  a  study  of  eighteen  years'  duration, 
ultraviolet  irradiation  was  reported  to  have  proved  its  worth  in  the  treat- 
ment of  diseases  of  the  eye.  Such  treatments,  for  example,  had  reduced 
the  proportion  of  losses  in  ulcus  serpens  from  30  to  6  per  cent.  Ultra- 
violet irradiations  likewise  had  produced  favorable  results  in  other  dis- 
eases of  the  cornea,  conjunctiva  and  sclera.  Excellent  results  have  been 
reported  in  the  treatment  of  corneal  ulcers  by  accurately  localized  ultra- 
violet irradiation. 

Ultraviolet  radiation  often  is  of  benefit  in  the  treatment  of  tuberculous 
lesions  of  the  eye.  A  study  of  the  combined  use  of  local  and  general 
ultraviolet  irradiation  for  the  treatment  of  tuberculous  lesions  of  the  eye 
in  100  children  revealed  some  improvement  in  every  case. 

Diseases  of  the  Ear.  —  It  has  been  claimed  that  irradiation  by  means  of 
a  "Kromayer"  lamp  with  a  small  quartz  rod  in  many  instances  will 
abort  furunculosis  of  the  external  auditory  canal.  Combined  local  and 
general  ultraviolet  irradiations  have  been  reported  to  be  of  definite  value 
in  the  treatment  of  tuberculosis  of  the  middle  ear. 

There  is  little  evidence  that  ultraviolet  radiation  is  of  value  in  the 
treatment  of  chronic  otorrhea,  for  which  it  occasionally  has  been  recom- 
mended; it  has  been  pointed  out  that  even  a  thin  layer  of  mucus  or  pus 
will  filter  out  the  ultraviolet  rays  and  prevent  any  favorable  action. 

Diseases  of  the  Nose.  —  Ultraviolet  irradiation  has  been  recommended 
as  an  adjunct  to  the  surgical  removal  of  tuberculous  lesions  of  the  nose. 
It  likewise  has  been  said  that  ultraviolet  irradiation  is  of  value  in  the 
treatment  of  infected  wounds  and  of  certain  nasal  dermatoses,  and  its  use 
has  been  suggested  for  ulcerations  of  the  nose,  especially  septal  ulcers. 
Ultraviolet  rays  likewise  have  been  said  to  be  of  value  in  the  treatment 
of  lupus  of  the  nasal  mucosa. 

Diseases  of  the  Throat.  —  Combined  general  and  local  ultraviolet  ir- 
radiation has  been  recommended  in  the  treatment  of  tuberculous  laryn- 
gitis. Strandberg^"  reported  a  series  of  203  cases  of  tuberculous  laryngitis 
in  which  treatment  with  general  ultraviolet  irradiation  was  followed  by 
cauterization.  One  hundred  and  thirteen  patients  were  reported  as  cured 
of  the  disease  of  the  larynx,  and  the  majority  of  the  others  were  said  to 
have  improved.  Thomson^^  challenged  these  results  and  said  that  32 
patients,  who  had  pulmonary  tuberculosis,  had  been  treated  according 
to  the  Finsen  plan  without  any  striking  evidence  of  benefit.  In  only  two 
or  three  of  these  cases  could  some  improvement  be  claimed. 

Stevenson'2  observed  320  cases  of  tuberculous  laryngitis.    Thirty-eight 

Vol.  I.  941 


ACTION  AND   USES  OF   RADIANT   ENERGY       8io  (i) 

of  the  patients  obtained  clinical  cure,  loi  were  improved,  8i  were  unim- 
proved, 59  were  worse,  and  41  had  died.  All  of  Stevenson's  patients  re- 
ceived routine  sanatorium  care,  vocal  rest  and  various  local  applications 
to  the  throat  as  well  as  ultraviolet  irradiation.  It  is  impossible,  therefore, 
to  say  which  was  the  most  important  factor  in  treatment. 

In  a  study  of  452  cases  of  pulmonary  tuberculosis  tuberculous  laryn- 
gitis was  present  in  19.2  per  cent,  of  the  cases.  It  was  felt  that  reflected 
sunlight  was  of  value  occasionally  in  supervised  cases,  particularly  during 
the  early  stages.  It  would  seem  that  in  tuberculous  laryngitis  general 
and  local  ultraviolet  irradiation  in  conjunction  with  routine  care  may  be 
of  some  value  in  selected  cases  and  certainly  is  worthy  of  trial.  Several 
observers  have  felt  that  the  local  applications  of  ultraviolet  light  were  a 
valuable  adjunct. 

Diseases  of  the  Skin.  —  In  no  phase  of  ultraviolet  therapy  have  there 
been  more  irrational  and  hyperenthusiastic  claims  than  in  that  dealing 
with  treatment  for  cutaneous  diseases.  In  a  bewildering  mass  of  hastily 
written  literature  concerning  ultraviolet  therapy  claims  are  made  that 
this  physical  agent  will  cure  almost  any  cutaneous  disease  "from  acne  to 
zoster^^". 

It  has  been  stated'*  that  among  the  diseases  of  the  skin  ultraviolet 
irradiation  acts  specifically  only  on  lupus  vulgaris  and  this  only,  when 
treatment  is  strictly  on  the  Finsen  principle.  Likewise  ultraviolet  irradia- 
tion may  have  a  favorable  action  in  other  dermatoses,  scrofuloderma, 
erythema  induratum,  psoriasis,  pustular  folliculitis,  indolent  ulcer,  furuncu- 
losis,  acne  vulgaris,  angioma  serpiginosum,  parapsoriasis  and  pityriasis 
rosea. 

Ultraviolet  irradiation  has  been  recommended  for  various  forms  of 
acne,  acne  conglobata,  acne  cachecticorum,  acne  varioliformis  and  partic- 
ularly, acne  vulgaris.  In  treatment  for  acne  vulgaris  it  generally  is  con- 
sidered best  to  produce  a  second  degree  erythema  of  the  entire  region 
covered  by  the  lesions;  this  will  be  followed  by  desquamation.  The  most 
satisfactory  results  are  obtained  in  the  early  stages  of  the  disease  when 
slight,  acute  inflammation  and  only  a  few  comedones  are  present.  Re- 
sponse to  treatment  often  is  slow.  Proper  dietetic  management  and  medi- 
cation should  be  used  in  conjunction  with  ultraviolet  irradiation.  Patients 
always  should  be  told  to  expect  severe  reddening  of  the  skin  from  the 
second  degree  erythemal  dose  which  is  to  be  administered.  They  fre- 
quently object  to  heavy  doses  of  ultraviolet  radiation  on  the  face  which  is 
a  common  site  of  the  lesions.  In  persistent  cases  of  acne  vulgaris,  it 
is  said,  irradiation  with  a  "cold  quartz"  lamp  often  frees  the  patient 
from  the  lesions  and  lessens  the  degree  of  scarring.     In  local  treatment 

Vol.  I.  941 


8io  (2)  PHYSICAL   MEDICINE 

for  acne  vulgaris,  particulariy  of  the  juvenile  type,  ultraviolet  irradiation 
in  erythemal  doses,  which  produces  exfoliation,  may  be  used  to  advantage 
in  conjunction  with  other  measures.  It  is  indicated  especially  for  pa- 
tients ten  to  fourteen  years  of  age  before  complete  development  of  adoles- 
cence, at  which  time  roentgen  therapy  is  contraindicated.  It  has  been 
said  that,  although  roentgen  rays  undoubtedly  are  best  in  local  treatment 
for  acne  vulgaris,  their  improper  use  often  is  followed  by  disastrous  re- 
sults. Ultraviolet  light  applied  locally  in  combination  with  astringent 
lotions  is  helpful  in  certain  cases. 

In  treatment  of  adenoma  sebaceum  the  use  of  blistering  doses  of  ultra- 
violet irradiation  has  been  recommended,  and  it  has  been  said  to  be  useful 
occasionally  for  this  purpose.  Erythema  of  second  or  third  degree  must 
be  produced  which  will  be  followed  by  marked  desquamation. 

It  has  been  reported  that  local  applications  of  moderate  doses  of  ul- 
traviolet radiation  may  improve  the  lesions  of  angioma  serpiginosum. 
Satisfactory  results  have  been  reported  in  treatment  by  means  of  ultra- 
violet irradiation  for  infected  granulating  regions  following  extensive  burns, 
in  preparation  for  Thiersch  grafts.  It  was  said  that  the  effect  of  such 
rays  on  these  wounds  might  be  attributed  to  the  following  factors;  (i)  a 
bactericidal  effect  on  the  organisms  on  the  surface,  (2)  production  of 
active  hyperemia  which  increased  nutrition  and  resistance  of  tissues 
locally  and  (3)  perhaps  a  stimulation  of  cell  growth. 

In  regard  to  treatment  for  cicatrices  heavy  doses  of  ultraviolet  radia- 
tion may  be  found  serviceable  in  the  removal  of  small  pitted  scars,  par- 
ticularly the  type  encountered  following  acne. 

Many  authors  have  reported  favorable  effects  from  treatment  for 
erysipelas  by  means  of  ultraviolet  irradiation.  Excellent  results  were 
reported  by  one  investigator,  who  said  that  each  of  91  patients,  who  had 
erysipelas,  was  given  a  single,  simple,  ultraviolet  treatment,  which  was 
inexpensive  and  without  danger.  The  results  were  believed  to  be  as 
satisfactory  as  those  to  be  obtained  from  the  use  of  antitoxin,  roentgen 
rays  or  any  other  accepted  method  of  treatment.  It  is  necessary  usually 
to  obtain  only  one  heavy  dose  of  erythema  of  second  degree  or  even  third 
degree  over  the  entire  lesion,  including  2  inches  (5  cm.)  of  normal  skin  in 
every  direction  around  the  borders  of  the  lesion.  The  common  error  in 
treatment  is  to  give  insufficient  exposure.  Fifteen  to  twenty  times  the 
minimal  erythemal  dose  often  should  be  administered.  Even  with  smaller 
doses  results  may  be  good.  Thus  one  author  reported  that  exposures  of 
only  fifteen  to  sixty  seconds  at  a  distance  of  20  to  30  inches  (51  to  76  cm.) 
to  a  mercury  quartz  lamp  in  10  cases  produced  results  that  were  better 
than  those  of  any  other  treatment  which  had  been  given.     It  was  stressed 

Vol.  I.  941 


ACTION  AND   USES  OF   RADIANT   ENERGY       8io  (3) 

that  treatment  should  be  begun  at  the  earUest  possible  moment,  especially 
before  the  lesion  has  had  time  to  extend  into  the  hair  or  to  the  external 
auditory  meatus. 

In  a  report  on  340  cases  of  erysipelas  of  all  types,  in  which  treatment 
with  ultraviolet  radiation  was  employed,  double  the  erythemal  dose  with 
the  hot  quartz  lamp  at  a  distance  of  only  8  inches  (20  cm.)  from  the  lesion 
or  twenty  times  the  erythemal  dose  with  a  "cold  quartz"  lamp  were  used. 
Twenty-seven  patients,  7.94  per  cent.,  died  of  erysipelas,  and  313  recovered. 
The  average  time  between  treatment  and  restoration  of  normal  tempera- 
ture was  3.9  days.  The  average  duration  from  the  time  of  treatment  to 
the  time  of  dismissal  was  8.67  days.  The  average  duration  from  onset  to 
dismissal  was  11.34  days.  It  was  concluded  that  ultraviolet  irradiation 
was  an  effective  treatment  for  erysipelas,  for  consistently  good  results 
were  obtained  in  this  study  which  covered  a  period  of  seventeen  years. 

The  following  technic  for  local  application  of  ultraviolet  rays  for  ery- 
sipelas has  been  suggested.  The  region  of  involvement  and  the  normal 
adjacent  skin,  at  least  2  inches  (5  cm.)  beyond  the  border  of  the  lesion, 
should  be  exposed  to  ultraviolet  radiation.  A  mercury  quartz  burner 
may  be  used.  The  lamp  is  permitted  to  run  for  ten  minutes  before  treat- 
ment is  begun  in  order  that  the  lamp  may  reach  its  maximal  efficiency. 
The  rays  must  strike  the  diseased  region  and  the  adjacent  skin  at  right 
angles  to  its  surface  for  ten  minutes  at  a  distance  of  12  inches  (30  cm.) 
provided  the  erythemal  dose  of  the  lamp  is  approximately  one  minute  at 
that  distance.  For  infants  and  very  young  children  the  time  of  exposure 
may  be  reduced  to  five  minutes  and  occasionally,  to  three  minutes.  If 
the  lesion  of  erysipelas  shows  evidence  of  spreading,  a  second  treatment 
will  be  required.     Usually  one  intense  treatment  suffices. 

It  has  been  said  that  ultraviolet  irradiation  may  be  beneficial  in  treat- 
ment for  erythema  induratum.  Local  irradiation  also  may  improve  the 
lesions  of  pustular  folliculitis.  Although  it  has  been  said  that  ultraviolet 
radiations  are  of  questionable  value  for  furunculosis,  other  authorities 
have  believed  that  such  lesions  sometimes  may  be  improved  by  judicious 
irradiation. 

Concentrated  ultraviolet  irradiation  undoubtedly  is  the  best  local 
treatment  for  lupus  vulgaris.  The  carbon  arc  light  of  the  Finsen  type  is 
said  to  be  more  satisfactory  than  the  "Kromayer"  lamp.  It  has  been 
reported  that  cure  was  obtained  in  only  29  per  cent,  of  cases  when  a 
"Kromayer"  lamp  was  used  and  in  90  per  cent,  of  cases  when  a  carbon 
arc  lamp  was  used.  At  the  Finsen  Institute  during  a  period  of  ten  years 
treatment  was  given  in  957  cases  of  lupus  vulgaris.  In  735  of  these  cure 
apparently  resulted;   in  75  treatment  was  still  being  carried  out,  and  in 

Vol.  I.  941 


8io  (4)  PHYSICAL   MEDICINE 

147  adequate  treatment  had  failed,  for  one  reason  or  another,  to  be 
accompHshed.  If  this  latter  group  is  omitted,  there  are  810  cases,  in 
which  adequate  treatment  was  received,  and  in  735  of  these,  90.7  per  cent., 
the  lesions  apparently  were  cured.  Further  study  revealed  that  of  the 
735  patients,  who  received  adequate  treatment  and  apparently  were  cured, 
44  showed  signs  of  recurrence  later.  Nevertheless  the  results  were  ex- 
cellent. It  is  felt  that  ultraviolet  irradiation  still  may  be  considered  the 
standard  form  of  treatment  for  lupus  vulgaris. 

The  interesting  and  valuable  observation  has  been  made  that  in  cases 
of  lupus  vulgaris  the  tuberculous  skin  is  more  pervious  to  luminous  and 
to  ultraviolet  radiation  than  is  normal  skin.  The  energy  penetration 
becomes  relatively  greater  as  the  wavelengths  grow  shorter,  until  at  313 
millimicrons  the  tuberculous  skin  may  be  three  to  six  times  as  pervious 
as  normal  skin.  Thus,  greater  action  of  the  radiant  energy  on  the  dis- 
eased skin  is  to  be  presumed. 

In  cases  of  nevus  flammeus,  port  wine  mark,  ultraviolet  irradiations  may 
be  very  useful;  excellent  results  may  be  obtained  with  the  use  of  an  air- 
cooled  ultraviolet  lamp  and  thorough-going  blanching  may  be  produced 
readily.  Parapsoriasis  and  pernio  also  may  be  improved  by  ultraviolet 
irradiations. 

In  cases  of  pityriasis  rosea  in  conjunction  with  the  use  of  soothing 
lotions  such  as  calamine  lotion  or  mild  protective  ointments  such  as 
boric  acid,  zinc  oxide  or  2  per  cent,  sulfur  ointment  ultraviolet  irradiation 
may  be  used  routinely.  However,  ointments  and  oily  applications  some- 
times may  aggravate  the  condition,  and  calamine  lotion  without  phenol 
is  said  to  be  by  great  odds  the  best  local  application.  It  has  been  sug- 
gested also  that  erythemal  doses  of  ultraviolet  radiation  from  either 
"cold  quartz"  or  hot  quartz  lamps  are  too  irritating  and  are  unnecessary. 
However,  divided  suberythemal  doses  are  recommended,  and  they  usually 
quiet  the  itching  and  promote  exfoliation  of  the  lesions  within  two  or 
three  weeks.  Although  previously  I  have  recommended  the  production 
of  a  second  degree  erythema  in  order  to  obtain  desquamation,  I  now  feel 
that  the  suberythemal  doses  are  more  satisfactory.  As  I  pointed  out 
previously,  after  the  use  of  a  second  degree  erythema  the  itching,  fawn- 
colored  lesions  on  the  trunk  are  replaced  by  generalized  sunburn.  Be- 
cause the  disease  is  self-limited  and  because  the  discomfort  from  the 
sunburn  is  considerable,  it  might  be  preferable  to  use  other  palliative 
measures  and  permit  the  disease  to  run  its  course.  By  using  suberythemal 
doses  recovery  may  be  hastened  without  producing  any  discomfort  to  the 
patient;  this  procedure  is  advocated  as  an  adjunct  to  other  forms  of 
treatment. 

Vol.  I.  941 


ACTION   AND    USES  OF    RADIANT   ENERGY       8io  (5) 

Although  it  has  been  reported  that  ultraviolet  irradiation  may  cause 
improvement  or  may  be  injurious  in  cases  of  psoriasis,  nevertheless,  with 
judicious  applications,  ultraviolet  radiation  may  be  very  beneficial.  If 
the  affected  skin  is  covered  with  a  thin  film  of  crude  coal  tar  ointment  and 
then  irradiated  with  ultraviolet  light,  better  results  can  be  obtained  than 
by  the  use  of  either  one  of  these  agents  alone.  The  ointment  should 
consist  of  gr.  30  (2  gm.)  each  of  crude  coal  tar  and  pulverized  zinc  oxide, 
mixed  with  2  ounces  (56.7  gm.)  each  of  corn  starch  and  petrolatum. 

The  ointment  is  applied  to  the  patches  for  twenty-four  hours  and  then 
is  removed  with  olive  oil.  Vigorous  efforts  at  cleansing  are  postponed 
until  after  the  lesions  have  been  exposed  to  a  mercury  quartz  ultraviolet 
lamp.  Thus  a  thin  film  of  the  ointment  remains  on  the  lesion  during 
irradiation.  Only  after  ultraviolet  irradiation  may  the  patient  take  a 
bath  with  soap  and  water  or  oatmeal  and  soda  which  by  aiding  in  the 
removal  of  the  remaining  debris  enhances  the  effect  of  the  tar  and  light. 
The  light  usually  is  applied  at  a  distance  of  30  inches  (75  cm.)  for  one 
minute,  the  time  being  increased  one  minute  daily  for  three  or  four  days. 
If  the  patient  then  shows  no  signs  of  reaction,  the  time  of  irradiation  is 
increased  rapidly,  and  the  distance  between  the  lamp  and  the  lesion  is 
decreased. 

An  effort  is  made  to  avoid  any  marked  cutaneous  reaction,  but  an 
attempt  is  made  to  produce  tanning  as  soon  as  possible.  If  the  therapist 
is  acquainted  thoroughly  with  the  effectiveness  of  his  lamp,  and  if  he 
handles  it  deftly,  "it  should  be  possible  to  remove  all  patches  of  psoriasis 
in  practically  all  cases  in  from  three  to  four  weeks". 

Patients  who  have  psoriasis  are  likely  to  experience  the  development 
of  arthritis.  In  a  series  of  936  cases  of  psoriasis  studied  at  the  Mayo 
Clinic  arthritis  was  associated  with  133,  14  per  cent.,  of  them.  In  40  of 
these  133  cases  systematic  treatment  with  tar  and  ultraviolet  irradiation 
was  given.  The  eruption  responded  as  readily  in  these  cases  as  in  those 
in  which  arthritis  was  not  present.  It  was  a  striking  fact  that  in  about 
half  of  these  cases  the  active  symptoms  of  the  arthritis  entirely  disap- 
peared without  any  other  treatment. 

Employed  judiciously  a  combination  of  local  and  general  ultraviolet 
irradiation  may  be  of  benefit  to  scrofuloderma.  There  is  sufificient  evi- 
dence to  justify  the  statement  that  ultraviolet  irradiation  is  of  value  for 
certain  types  of  cutaneous  tuberculosis,  scrofuloderma. 

Indolent  ulcers  occasionally  may  be  caused  to  heal  more  rapidly  by  the 
use  of  erythemal  doses  of  ultraviolet  radiation  or  by  daily  exposures  to 
graduated  doses  of  solar  radiation.  In  regard  to  wounds,  particularly 
indolent  wounds,    the   use   of   unaltered   sunlight   has   been    recommended 

Vol.  I.  941 


8io  (6)  PHYSICAL   MEDICINE 

highly.  I  have  been  able  to  obtain  what  I  consider  to  be  comparable 
results  by  exposing  the  indolent  wound  first  to  a  radiant  heat  lamp  and 
then  to  a  mercury  quartz  lamp. 

There  is  a  difference  of  opinion  regarding  the  value  of  ultraviolet 
irradiation  for  about  thirty  additional  dermatoses. 

Miscellaneous  Diseases.  —  In  rickets  it  is  believed  that  ultraviolet 
irradiation  furthers  the  absorption  from  the  intestine  of  either  phosphorus 
or  calcium  or  both.  It  is  probable  that  the  hydrogen  ion  concentration  is 
the  limiting  factor  in  such  action.  A  number  of  investigators  have  shown 
that,  to  produce  beneficial  effects  in  the  treatment  of  rickets,  it  is  neces- 
sary to  administer  only  comparatively  small  doses  of  effective  ultraviolet 
radiation. 

For  example,  a  single  weekly  exposure  to  one  erythemal  dose  of  ultra- 
violet rays  was  sufficient  to  produce  healing  of  rachitic  lesions  of  infants. 
Irradiations  from  a  mercury  quartz  lamp,  front  and  back,  for  four  to  five 
minutes  once  weekly,  until  approximately  lOO  minutes  of  exposure  had 
been  given,  was  sufficient  to  effect  cure  in  a  series  of  43  rachitic  nurslings 
so  treated. 

Heavy  doses  of  ultraviolet  light  did  not  prevent  rickets  in  rats,  which 
had  been  placed  on  a  rickets-producing  diet,  provided  they  were  pre- 
vented from  licking  their  fur  or  eating  their  excretions.  If,  however,  the 
rats  were  shaved,  the  skin  sterol  then  was  activated  by  irradiation,  ab- 
sorbed and  exerted  antirachitic  effects. 

It  has  been  shown  that  the  provitamins  D  exhibit  pronounced  ultra- 
violet absorption.  Of  the  eight  to  ten  provitamins  D,  which  are  said  to 
exist,  only  two,  ergosterol  and  7-dehydrocholesterol,  appear  to  be  very 
common.  When  irradiated,  these  provitamins  become  extremely  active, 
and  5  mgm.  of  either  is  equivalent  in  potency  to  i  liter  of  good  cod  liver 
oil.  Direct  irradiation  of  the  skin  by  ultraviolet  rays  may  be  specific 
in  the  treatment  of  rickets. 

Results  comparable  to  those  obtained  in  the  treatment  of  rickets  may 
be  obtained  also  by  the  use  of  ultraviolet  irradiation  in  cases  of  tetany  and 
spasmophilia. 

Among  the  unusual  uses  of  ultraviolet  irradiation  may  be  mentioned 
its  employment  for  diagnostic  purposes,  for  the  identification  marking  of 
newborn  infants,  for  the  purpose  of  producing  hardening  of  the  nipples 
prenatally  and  for  the  sterilization  of  air  in  operating  rooms.  It  has  been 
pointed  out  that  prenatal  irradiation  and  the  irradiation  of  the  nursing 
mother  are  efficacious  in  the  prevention  of  rickets  in  the  child,  and  that 
direct  irradiation  of  cows  will  impart  an  antirachitic  potency  to  their 
milk. 

Vol.  I.  941 


SUMMARY   OF    RADIANT   ENERGY  8io  (7) 

Contraindications  to  the  Application  of  Ultravioi-et 
Radiant  Energy 

Ultraviolet  irradiation  is  contraindicated  in  the  presence  of  cardiac 
insufficiency,  valvular  heart  disease,  advanced  myocarditis,  arteriosclero- 
sis, nephritis,  advanced  bilateral  renal  tuberculosis  with  impending  uremia 
and  pulmonary  tuberculosis  of  the  advancing  exudative  type. 

It  sometimes  is  contended  that  previous  exposure  to  roentgen  rays 
contraindicates  subsequent  exposure  to  ultraviolet  radiation.  The  idea 
probably  arises  from  the  fear  of  a  possible  cumulative  action  produced  by 
the  latent  erythema  from  the  roentgen  rays  added  to  the  erythema  from 
the  ultraviolet  rays.  With  this  exception  there  is  no  apparent  contrain- 
dication to  combining  the  two  procedures.  Recently  Ellis  and  Kirby- 
Smith^*  studied  11  patients  who  had  been  given  from  10  to  16  one-third 
erythemal  doses  of  roentgen  rays  and  from  4  to  20  erythemal  doses  of 
ultraviolet  rays.  None  showed  any  evidence  of  roentgen  ray  dermatitis. 
They  concluded  that  roentgen  therapy  has  simply  an  additional  action 
separate  from  the  effect  of  the  ultraviolet  radiation  on  the  skin.  For 
example,  if  R  represents  the  permanent  or  late  effect  of  the  roentgen  rays 
and  A  the  permanent  actinic  cutaneous  change,  then  the  total  late  changes 
will  equal  R  plus  A.  When  roentgen  (R)  and  ultraviolet  irradiations  (A) 
are  given  simultaneously,  alternately  or  later,  neither  exerts  a  beneficial 
or  deleterious  effect  on  the  other,  but  there  is  only  a  summation  of  the 
effect  of  one  plus  that  of  the  other. 

Ultraviolet  irradiation  may  cause  an  exacerbation,  provoke  an  attack 
or  produce  other  injurious  effects  in  such  cutaneous  lesions  as  eczema, 
lupus  erythematosus,  herpes  simplex,  erythema  solare  perstans,  xeroderma 
pigmentosum,  freckles,  atrophy,  keratoses  and  permaturely  senile  skin. 

Exposures  to  ultraviolet  radiation  should  not  be  employed  for  tuber- 
culosis of  the  suprarenal  glands  or  for  certain  types  of  tracheobronchial 
adenitis.  Such  exposures  are  contraindicated  also  in  the  presence  of  hy- 
perthyroidism and  diabetes,  because  pruritus  and  heightened  irritability 
may  result.  Still  other  contraindications  to  the  use  of  ultraviolet  irradia- 
tion are  advanced  cachexia,  inanition,  extreme  age  and  acute  forms  of 
generalized  dermatitis. 

Summary  of  Data  on  Radiant  Energy 

Ultraviolet  irradiation  has  been  used  extensively  but  indiscriminately 
in  the  practice  of  medicine.  However,  in  a  rather  large  number  of  con- 
ditions  the   evidence   indicates   that   ultraviolet   irradiation   is,   or   gives 

Vol.  I.  941 


8io  (8)  PHYSICAL    MEDICINE 

promise  of  being,  valuable.  Among  these  conditions  may  be  mentioned 
tuberculous  peritonitis  and  enteritis,  calcium  deficiency  diseases,  secondary 
anemia,  carbon  monoxide  poisoning,  pulmonary  tuberculosis,  tuberculosis 
of  bones  and  joints,  atrophic  and  hypertrophic  arthritis,  tuberculosis  of 
the  genito-urinary  tract,  ulcus  serpens,  corneal  ulcer,  tuberculous  lesions 
of  the  eye,  ear  or  nose,  nasal  ulcerations,  tuberculous  laryngitis,  certain 
cutaneous  diseases,  rickets,  tetany  and  spasmophilia. 

BIBLIOGRAPHY   OF   RADIANT   ENERGY 

1.  KRUSEN,  F.  H.:    Light  Therapy,  Ed.  2,  Hoeber,  New  York,   1937. 

2.  KRUSEN,  F.  H.:    Medical  application  of  ultraviolet  radiant  energy,  Ann.  Int. 

Med.,  1940,  XIV,  641. 

3.  LAURENS,  H.:    The  Physiological  Effects  of  Radiant  Energy,  The  Chemical 

Catalog  Co.,  New  York,  1933. 

4.  MAUGHAN,  G.  H.  and  SMILEY,  D.  F. :    Irradiations  from  a  quartz-mercury- 

vapor  lamp  as  a  factor  in  the  control  of  common  colds,  Am.  Jour.  Hyg., 
1929,  IX,  466. 

5.  ZERFOSS,  T.  B.:    The  management  of  colds,  Journal-Lancet,   1935,  LV,  792. 

6.  FANTUS,  B.:    The   therapy  of   the   Cook   County   Hospital,  Jour.  Am.  Med. 

Assoc,  1936,  CVI,  375. 

7.  HILL,  C.  M.  and  CLARK,  J.   H.:    The  effect  of  ultraviolet  radiation  on  re- 

sistance to  infection.  Am.  Jour.  Hyg-,  1927,  VII,  448. 

8.  KRUSEN,   F.   H.:    Heliotherapy  in  the  treatment  of  pulmonary  tuberculosis, 

Am.  Rev.  Tuberc,  1927,  XVI,  180. 

9.  BERNHARD,  O.:    Quoted  by  Laurens,  H.l 

ID.  STRANDBERG,  O. :  Traitement  phototherapique  de  la  tuberculose  du  larynx. 
Traitement  special  par  bains  de  lumiere  chimiques  artificiels,  combine  avec 
un  traitement  chirurgical  intralarynge,  Ann.  d.  Mai.  de  I'Oreille,  du  Larynx, 
1927,  XLVI,  653. 

11.  THOMSON,  St.  C:    Quoted  by  Stevenson,  R.  S}\ 

12.  STEVENSON,  R.  S.:   The  treatment  of  tuberculosis  of  the  larynx,  Brit.  Med. 

Jour.,  1933,  II,  960. 

13.  WILLIAMS,    H.    B.:    The   need  of  research   in   physical   therapy.    In   Vol.    I, 

pp.   1-3,  Principles  and  Practice  of  Physical  Therapy,  Prior,  Hagerstown, 
Maryland,  1934. 

14.  COUNCIL  ON  PHYSICAL  THERAPY:    Regulations  to  govern  advertising  of 

ultraviolet    generators    to    the    medical    profession    only.    Jour.  Am.  Med. 
Assoc,   1932,  XCVIII,  400. 

15.  ELLIS,   F.   A.   and   KIRBY-SMITH,   H.:    Effect  of  ultraviolet  radiation  on 

roentgen  rays:    do  ultraviolet  rays  have  deleterious  effect  on  roentgen  rays 
when  applied  to  the  skin?     Arch.  Dermat.  and  Syph.,  1940,  XLII,  466. 

Sept.  I,  1941. 

Vol.  L  941 


METHODS  OF   APPLYING   HYDROTHERAPY       8io  (9) 

HYDROTHERAPY 

Although  it  is  one  of  the  oldest  forms  of  therapy  and  one  which  often 
can  be  employed  to  advantage,  hydrotherapy  has  been  neglected  recently. 
Interest  in  the  employment  of  water  for  therapeutic  purposes  has  waxed 
and  waned  throughout  the  centuries  but  never  has  ceased  entirely. 
Baruch'  said:  "Of  all  remedial  agents  in  use  since  the  dawn  of  medicine, 
water  is  the  only  one  that  has  survived  all  the  vicissitudes  of  doctrinal 
changes  because  its  rise  or  fall  was  always  contemporaneous  with  the  rise 
and  fall  of  intelligence  among  medical  men".  If  this  is  true,  we  modern 
physicians  should  look  to  our  laurels  and  inquire  into  the  present  state 
of  our  collective  intelligence.  The  current  medical  literature  is  woefully 
lacking  in  careful,  scientific  evaluations  of  the  various  phases  of  hydro- 
therapy. 

It  has  been  said:  "Hydrotherapy  includes  the  application  of  water  in 
any  form  from  the  solid  and  fluid  to  vapor,  from  ice  to  steam,  internally 
and  externally".     Water  can  be  applied  either  locally  or  generally. 

Methods  of  Applying  Hydrotherapy 

Local  Application.  — Among  the  methods  of  applying  water  locally  for 
therapeutic  purposes  can  be  mentioned  local  baths,  sitz  baths,  contrast 
baths,  whirlpool  baths,  local  douches,  irrigations  and  compresses. 

Local  Baths.  The  arm,  hand,  leg,  foot  or  other  local  region  of  the 
body  can  be  immersed  in  water  at  different  temperatures  to  cause  local 
effects  which  uusally  are  of  a  thermal  or  mechanical  nature.  Baths  for 
the  extremities  usually  are  administered  in  specially  shaped  containers 
which  conform  to  the  shape  of  the  limb.  A  large  oval  dishpan  can  be 
used  for  the  arm  and  a  large  bucket  or  tub  for  the  leg.  In  the  so-called 
half  bath  only  the  pelvis,  hips  and  lower  extremities  are  immersed  in 
water  contained  in  an  ordinary  bath  tub. 

In  the  sitz  {hip)  hath  the  patient  sits  in  water  with  only  the  hips, 
pelvis  and  external  genitalia  immersed.  In  institutions  special  tubs  are 
employed  for  administration  of  these  baths,  but  in  the  home  a  wash  tub 
can  be  substituted. 

Alternate  applications  of  hot  and  cold  water,  contrast  baths,  to  the 
extremities  are  very  useful  in  treatment  for  hypertrophic  arthritis  and  for 
certain  circulatory  diseases.  The  usual  plan  of  alternately  immersing  the 
part  in  hot  and  then  in  cold  water  for  intervals  of  one  minute  is  not  so 
satisfactory  as  are  immersions  for  longer  periods  of  time.  Woodmansey 
and  his  associates-  in  England  found  the  best  circulatory  responses  when 

Vol.  I.  941 


8io(io)  PHYSICAL   MEDICINE 

the  hot  water  was  applied  for  six  minutes  and  the  cold  water  for  four 
minutes.  Our  American  patients,  possibly  because  they  are  accustomed 
to  warmer  houses,  dislike  the  more  prolonged  periods  of  cold. 

Checking  the  work  of  Woodmansey  I  found  that  patients  in  this 
country  responded  best  to  a  routine  which  employed  either  five  minutes 
of  heat  and  two  minutes  of  cold  or  four  minutes  of  heat  and  one  minute  of 
cold.  To  obtain  the  best  vascular  response  the  patient  always  should 
start  and  end  with  the  hot  water.  The  cold  water  should  be  kept  at  a 
temperature  of  50°  to  65°  F.  (10°  to  18.3°  C.)  and  the  hot  water  at  100° 
to  1 10°  F.  (37.8°  to  43.3°  C.)  If  the  first  routine  is  employed,  the  treatment 
should  last  for  either  19  or  26  minutes,  thus  5-2-5-2-5  or  5-2-5-2-5-2-5. 
If  the  latter  procedure  is  employed,  treatments  will  require  19  or  24  min- 
utes, thus  4-1-4-1-4-1-4  or  4-1-4-1-4-1-4-1-4. 

Baths  of  whirling  aerated  water,  whirlpool  baths,  at  a  temperature  of 
1 10°  F,  (43.3°  C.)  have  been  employed  extensively  in  civilian  hospitals 
for  increasing  the  peripheral  circulation  of  the  extremities.  These  baths, 
which  were  developed  during  the  World  War  of  1914-1918,  still  are  con- 
sidered to  be  extremely  useful,  especially  in  the  management  of  fractures 
of  the  extremities.  Specifications  for  the  construction  of  a  simple,  "home- 
made", whirlpool  bath  are  illustrated  in  Fig.  23.  For  institutional  work 
specially  shaped  whirlpool  baths  are  available  for  immersion  of  the  leg; 
there  is  another  type  which  is  raised  on  a  pedestal  for  immersion  of  the 
arm.  Portable  whirlpool  baths  also  are  available.  These  contain  an  im- 
mersion heater  and  a  mechanical  electrically  operated  device  for  agitating 
and  aerating  the  water. 

Various  sprays  and  douches  can  be  employed  therapeutically.  The  or- 
dinary bath  spray,  sometimes  called  a  "rose  spray",  can  be  used  to  shower 
a  local  region  with  hot  or  cold  water,  or  it  can  be  employed  to  administer 
contrast  baths  to  regions,  such  as  a  shoulder,  which  cannot  be  immersed 
readily  in  a  tub. 

The  jet  douche  is  a  stream  of  water  projected  from  an  ordinary  hose 
nozzle.  If  the  water  from  such  a  nozzle  is  spread  in  the  shape  of  a  fan  by 
placing  a  finger  over  the  opening,  it  is  called  a  "/a«  douche".  If  the 
circular  aperture  in  the  nozzle  is  extremely  small  so  that  a  very  fine, 
forceful  stream  of  water  is  projected  on  the  body,  it  is  spoken  of  as  a 
''filiform  douche".  Such  a  stream  may  be  sufficiently  forceful  to  destroy 
surface  epithelium  and  even  to  cause  bleeding. 

Irrigations  are  used  chiefly  for  flushing  of  various  bodily  cavities, 
that  is,  the  colon,  vagina,  ear,  nose,  throat,  urinary  bladder  or  stomach. 
In  the  few  instances  in  which  irrigation  of  the  colon  is  necessary,  the 
physician  can  employ  an  ordinary  bed,  a  plain  glass  irrigation  jar  on  a 

Vol.  I.  941 


METHODS  OF  APPLYING  HYDROTHERAPY      8io  (ii) 

stand,  a  rectal  tube  (no.  34,  French),  a  Y  tube  with  two  clamps  and  a 
large  closed  jar  to  receive  the  return  flow.  This  simple  equipment  is 
equally  as  effectual  as  the  elaborate  colonic  irrigation  tables  covered  with 
chrome  metal  and  fancy  gadgets  which  so  frequently  are  marketed  for 
this  purpose. 

For  irrigation  of  the  vagina  the  usual  irrigation  can  or  fountain  syringe 

Home  Made 
MiiiRLPooL  Bath 

1e  hal  and  ooM  valer  napply 


Copper  WashboiI«r 

Fig.  23.  Specifications  for  the  construction  of  a  homemade  whirlpool  bath  (Courtesy 
of  the  Council  on  Physical  Therapy  of  the  American  Medical  Association). 

with  a  hard  rubber  tip,  which  is  sufficiently  large  to  prevent  its  passage 
into  the  cervical  canal,  can  be  employed. 

For  irrigation  of  the  ear,  nose  or  throat  the  usual  irrigation  can  or 
rubber  bag  and  tubing  can  be  employed.  A  very  satisfactory  irrigation 
tip  can  be  made  by  inserting  the  glass  portion  of  an  ordinary  eye  dropper 
into  the  end  of  the  tubing.  Irrigation  of  the  bladder  is  performed  by 
connecting  the  fountain  syringe  to  an  ordinary  urethral  catheter. 

Finally  irrigation  of  the  stomach  can  be  accomplished  by  the  employ- 
ment of  one  of  several  types  of  tubes.  The  large  rubber  stomach  tube, 
which  varies  in  caliber  from  no.  12  to  no.  30,  French,  can  be  used.    Or  a 

Vol.  I.  941 


8io  (12)  PHYSICAL   MEDICINE 

large,  no.  30,  French,  Boas  tube,  a  nasal  catheter  with  a  soft  rubber  tip 
or  a  small  caliber  Rehfuss  tube  with  a  metal  tip  can  be  employed.  Fluids 
can  be  introduced  through  a  funnel  or  by  means  of  a  syringe  and  can  be 
removed  by  siphonage  or  by  means  of  the  syringe. 

Cloths  partially  wrung  out  after  dipping  in  hot  or  cold  water  can  be 
applied  to  some  region  of  the  body  to  produce  a  local  circulatory  reaction. 
These  are  spoken  of  as  ''compresses''  or  ''packs''. 

General  Application.  —  Among  the  methods  for  the  general  application 
of  water  can  be  mentioned  baths,  including  full  baths,  brine  baths,  effer- 
vescent baths  and  bland  baths,  Hubbard  tanks,  pools,  showers,  douches 
and  packs. 

A  cold  plunge  in  a  full  hath  at  a  temperature  of  50°  F.  (10°  C.)  occa- 
sionally is  employed  as  a  powerful  excitant.  The  tepid  full  bath  at 
temperatures  between  80°  and  92°  F.  (26.7°  and  33.3°  C.)  sometimes  is 
used  therapeutically.  A  neutral  bath  is  one  which  is  kept  at  a  tempera- 
ture of  from  92°  to  97°  F.  (33.3°  to  36.1°  C.)  while  the  hot  bath  is  applied 
at  temperatures  between  98°  and  108°  F.  (36.7°  and  42.2°  C.)  Continuous 
full  baths  sometimes  are  employed.  They  are  kept  at  neutral  tempera- 
ture, and  the  patient  lies  on  a  canvas  hammock  which  is  beneath  the 
water  in  a  large  tub. 

The  chief  advantage  of  the  brine  bath  is  its  buoyancy.  It  usually 
contains  from  5  to  30  pounds,  2.3  to  13.6  kg.,  of  sodium  chloride  to  40 
gallons,  160  liters,  of  water.  Little  salt  is  absorbed  through  the  skin. 
It  is  employed  usually  for  administration  of  certain  types  of  underwater 
exercise. 

Baths  containing  carbonated  water,  effervescent  baths,  commonly  known 
as  carbon  dioxide  or  "Nauheim"  baths,  occasionally  are  employed 
in  treatment  of  certain  types  of  cardiac  disease.  Usually  2  pound, 
0.2  kg.,  of  sodium  bicarbonate  is  placed  in  a  tubful  of  salt  water.  Then 
six  or  eight  large  tablets  of  specially  prepared  acid  sodium  sulfate  are 
arranged  along  the  floor  of  the  tub.  A  chemical  reaction  follows  which 
causes  the  liberation  in  the  water  of  large  quantities  of  carbon  dioxide. 
The  patient  then  is  immersed  in  this  bath. 

Sometimes  oxygen  is  bubbled  into  a  tub  of  water  through  rattan  reeds 
to  provide  an  "oxygen  bath".  This  type  of  effervescent  bath  was 
recommended  by  Nylin^. 

Sometimes,  soothing  or  bland  baths  are  used  in  treatment  of  certain 
acute  inflammations  of  the  skin.  They  usually  are  kept  at  neutral  tem- 
perature, and  soothing  medication  is  added  to  the  water.  A  suitable 
bland  bath  can  be  prepared  by  adding  to  the  full,  neutral  temperature 
bath  a  decoction  consisting  of  5  pounds  (2.3  kg.)  of  starch  in    i   gallon 

Vol.  I.  941 


PHYSICAL   PRINCIPLES   OF   HYDROTHERAPY     8io  (13) 

(4  liters)  of  water  or  3  pounds  (1.4  kg.)  of  wheat  bran  in  the  same  amount 
of  water. 

In  order  that  underwater  exercises  can  be  administered  easily  a 
special  butterfly-shaped  tank  has  been  constructed.  This  kind  of  tank, 
usually  called  a  ''Hubbard  tank",  now  is  employed  extensively  in  the 
various  hospitals  of  the  United  States.  A  simple  type  can  be  con- 
structed for  home  use;  specifications  are  obtainable  from  the  Council 
on  Physical  Therapy  of  the  American  Medical  Association. 

Therapeutic  pools  have  been  developed  to  a  high  degree  of  efficiency. 
They  are  employed  extensively  for  underwater  exercises  and  can  be  found 
in  many  large  hospitals,  schools  for  crippled  children  and  orthopedic 
institutions. 

The  overhead  shower  bath,  often  called  a  "rain  douche'',  and  the 
needle  shower  sometimes  are  employed  therapeutically.  The  latter  is 
composed  of  semicircles  of  shower  heads  which  spray  many  fine,  forceful 
streams  of  water  onto  the  surface  of  the  body.  The  pressure  of  the  water 
causes  the  needle-like  streamlets  to  sting  the  skin;  hence  the  designation 
"needle  shower". 

If  the  surface  of  the  body  is  sprayed  alternately  by  forceful  jets  of 
hot  and  cold  water,  the  procedure  is  called  a  "Scotch  douche".  This 
treatment,  when  properly  applied  by  a  skillful  individual,  has  a  dis- 
tinctly invigorating  and  refreshing  effect. 

The  full  wet  pack,  the  blanket  pack  and  the  towel  pack  all  have  been 
employed  therapeutically.  In  each  the  patient  is  wrapped  in  cold  or 
hot  moist  coverings.  Usually  the  patient  is  wrapped  in  a  cold,  wet 
covering  and  then  quickly  enveloped  in  warm  coverings.  A  reactive 
hyperemia  occurs,  and  he  soon  feels  warm  and  begins  to  perspire.  As  the 
patient  remains  in  the  pack,  it  finally  begins  to  produce  a  distinctly  seda- 
tive effect. 

Physical  Principles  Concerned  in  the  Employment 
OF  Hydrotherapy 

Water  solidifies  at  32°  F.  (o°C.);  as  ice  it  can  be  applied  locally. 
Water  occasionally  is  applied  locally  through  a  jet  in  its  gaseous  form, 
steam.  However,  in  most  instances  water  is  applied  in  its  liquid  form 
when  local  effects  are  desired.  Because  of  this  flexibility  of  application 
water  often  is  applied  generally  in  solid,  liquid  or  gaseous  form.  A  general 
application  of  the  solid  form  is  the  ice  pack,  of  the  liquid  form  the  full 
bath  and  of  the  gaseous  form  the  steam  bath. 

Water  is  an  excellent  medium  for  producing,  by  conduction,  changes  in 

Vol.  I.  941 


8io  (14)  PHYSICAL   MEDICINE 

the  temperature  of  the  bodily  tissues.  It  is  said  that  it  imparts  its  tem- 
perature to  bodily  tissue  more  readily  than  does  air  at  the  same  tempera- 
ture. A  sensation  of  chilliness  will  be  observed  much  more  rapidly  by 
anyone  lying  quietly  in  a  tub  of  still  water  at  80°  F.  (26.7°  C.)  than  by 
anyone  lying  in  still  air  at  the  same  temperature.  Also  water  has  a  high 
specific  heat,  that  is,  a  large  amount  of  heat  is  required  to  raise  its  tem- 
perature. Conversely,  when  it  cools,  it  liberates  a  large  amount  of  heat 
to  substances  with  which  it  is  in  contact.  Therefore,  water  is  a  very  satis- 
factory means  of  applying  conductive  heat. 

Hydrotherapeutic  procedures  can  cause  mechanical  as  well  as  thermal 
effects.  The  impact  of  water  applied  under  pressure  to  the  skin  will  tend 
to  have  a  stimulating  effect  on  the  sensory  nerve  endings.  A  shower  bath 
generally  is  considered  to  be  more  stimulating  and  refreshing  than  a  tub 
bath. 

Action  and  Uses  of  Hydrotherapy 

With  regard  to  the  local  effects  of  hydrotherapy  one  of  the  most  in- 
teresting of  the  recent  observations  is  that  of  Blair^.  His  studies  on  the 
physiological  effects  of  alternate  increase  and  decrease  of  the  blood  supply 
may  aid  in  explaining  the  value  of  contrast  baths  in  the  treatment  of 
fractures.  Furthermore  Blair's  observations  may  explain  in  part  the  rea- 
son for  the  varied  opinions  concerning  the  effect  of  hyperemia  on  calcifi- 
cation of  bone.  He  concluded  that  it  was  the  alternate  increase  and 
decrease  in  the  volume  of  blood,  which  promoted  calcification  of  bone, 
whereas  prolonged  hyperemia  produced  decalcification  of  bone,  and  pro- 
longed ischemia  caused  calcium  deposition  and  ossification. 

Normally  the  volume  of  blood  reaching  the  bones  of  the  extremities  is 
varied  by  the  alternate  contraction  and  relaxation  of  muscles  which  take 
place  during  the  usual  activity  of  the  part.  Following  a  fracture  pro- 
longed immobilization  prevents  this  activity.  Blair  concluded  that 
contrast  baths  which  have  been  used  for  years  "to  hasten  healing  of 
fractures"  probably  caused  "an  alternation  of  blood  supply  to  the  part" 
and  were  advantageous  because  "alternating  ischemia  and  hyperemia 
maintain  normal  calcification  of  bone".  If  Blair's  observations  are  correct, 
then  contrast  baths  followed  by  massage  and  muscle  setting  exercises, 
alternate  static  contraction  and  relaxation  of  muscles,  should  be  particu- 
larly effective  in  promoting  healing  and  calcification  of  fractures. 

It  has  been  pointed  out  by  McClellan*  that  hydrotherapeutic  proce- 
dures cause  chiefly  thermal  and  mechanical  stimulation.  This  stimulation 
acts  as  an  irritant  to  the  sensory  nerve  endings  and  may  produce  a  re- 

VoL.  I.  941 


ACTION   AND   USES  OF   HYDROTHERAPY        8io  (15) 

sponse  locally  by  reflex  action.  The  local  reaction  to  cold  water  is  con- 
traction of  elastic  and  muscular  fibers  in  the  cutaneous  and  subcutaneous 
regions,  which  results  in  ischemia.  When  the  application  of  cold  ceases, 
the  fibers  relax  with  the  result  that  hyperemia  occurs.  Hot  applications 
tend  to  result  in  an  atonic  reaction  and  cold  applications  in  a  tonic  reac- 
tion. 

The  chief  effect  of  generalized  application  of  water  is  thermal.  The 
bodily  temperature  will  tend  to  rise  or  fall  according  to  the  temperature 
of  the  bath.  The  physiological  effects  of  general  exposure  to  heat  or  to 
cold  already  have  been  discussed  in  the  sections  dealing  with  applications 
of  heat  and  cold. 

Most  writers  on  hydrotherapy  stress  the  importance  of  obtaining  a 
good  "reaction".  The  "action"  caused  by  brief  applications  of  cold 
water  consists  of  peripheral  vasoconstriction,  pallor,  chilliness,  shivering 
and  increases  in  respiratory  and  pulse  rates.  The  "reaction",  which 
starts  immediately  and  lasts  for  about  twenty  minutes,  consists  of  periph- 
eral vasodilatation,  redness  of  the  skin,  warmth,  relaxation  and  slowing 
of  the  respiratory  and  pulse  rates.  Likewise  a  "reaction"  may  be  noted 
following  a  brief  application  of  hot  water.  This  reaction  has  been  said^ 
to  consist  of  muscular  relaxation,  lowered  arterial  tension  and  increase 
in  the  pulse  rate  with  shallow  respirations.  In  order  to  produce  a  marked 
hyperemia,  alternate  applications  of  hot  and  cold  water  often  are  recom- 
mended. 

Cold  baths  increase  the  general  metabolic  rate  and  the  amount  of  oxy- 
gen inspired.  Hot  baths  also  will  increase  the  metabolic  rate,  if  they  are 
administered  for  a  period  which  is  sufficiently  long  to  raise  the  systemic 
temperature,  but  the  amount  of  oxygen  which  is  inspired  will  be  de- 
creased. 

Local  Application.  —  Warm  or  hot  local  baths  are  applied  to  the  upper 
or  to  the  lower  extremity  in  treatment  of  arthritis,  burns,  cellulitis,  circu- 
latory diseases,  contusions,  sprains  and  infected  wounds.  Cold  foot 
baths  have  been  recommended  in  treatment  of  bromidrosis  and  for  per- 
sistent coldness  of  the  feet.  Cold  sitz  baths  have  been  recommended  in 
treatment  of  such  conditions  as  amenorrhea,  prostatorrhea,  atony  of  the 
bladder,  atonic  constipation  and  sexual  impotence.  The  hot  sitz  baths 
have  been  suggested  in  treatment  of  dysmenorrhea,  amenorrhea,  pros- 
tatitis, tenesmus,  ureteral  colic,  pelvic  inflammation  and  gluteal  fibrositis. 
Contrast  baths  are  especially  useful  in  treatment  of  hypertrophic 
arthritis  of  the  hands  and  feet  and  in  the  management  of  fractures, 
sprains  and  contusions.  Such  baths  have  been  employed  also  for  periph- 
eral vascular  disease. 

Vol.  I.  941 


8io  (i6)  PHYSICAL   MEDICINE 

In  the  auxiliary  treatment  of  fractures  of  the  extremities  after  re- 
moval of  dressings  whirlpool  baths  often  are  valuable.  This  type  of 
bath  improves  circulation,  relaxes  muscles  and  seems  to  have  a  sedative 
effect,  thus  preparing  the  part  for  subsequent  massage  and  exercise.  In- 
dications for  use  of  whirlpool  baths  are  much  the  same  as  those  for  the 
contrast  baths.  Whirlpool  baths,  too,  are  used  in  treatment  of  traumatic 
lesions,  such  as  sprains,  contusions,  dislocations  and  of  arthritis,  periph- 
eral vascular  diseases  and  infected  wounds  of  the  extremities. 

Warm  or  hot  irrigations  of  the  ear,  nose  or  throat  are  employed  to 
relieve  inflammation  and  to  remove  exudate  in  the  presence  of  such  con- 
ditions as  otitis  media,  furunculosis  of  the  external  auditory  canal,  chronic 
rhinitis,  acute  nasopharyngitis  or  peritonsillar  abscess. 

Irrigations  of  the  stomach  are  used  for  relief  of  gastric  retention  in 
association  with  pyloric  stenosis  or  carcinoma.  They  have  been  employed 
also  to  remove  recently  ingested  poisons.  Vaginal  irrigations  often  are 
indicated  in  the  management  of  leucorrhea,  vaginitis,  endocervicitis,  en- 
dometritis and  pelvic  inflammatory  disease. 

There  are  very  few  indications  for  the  use  of  colonic  irrigations.  It  is 
possible  that  they  may  be  useful  occasionally  for  removal  of  masses  of  im- 
pacted feces  from  the  lower  part  of  the  bowel.  Such  irrigations  should 
not  be  employed  routinely.  Even  occasional  irrigations  rarely  are  in- 
dicated. 

Hot  compresses  are  employed,  at  times,  in  treatment  of  muscular 
spasm  or  of  acute  inflammatory  processes.  Cold  compresses  sometimes 
are  applied  over  the  precordium  in  treatment  of  tachycardia  and  cardiac 
neurosis. 

General  Application.  —  The  cold  full  bath  has  been  recommended 
to  improve  functional  activity,  to  stimulate  general  metabolism  and  to 
combat  the  debility  associated  with  sedentary  living.  It  was  recom- 
mended by  Brand  in  treatment  of  typhoid  fever.  The  tepid  bath  has 
been  employed  chiefly  as  a  sedative  or  to  combat  excessive  febrile 
reactions.  Neutral  baths  are  used  occasionally  to  treat  insomnia  or  to 
allay  nervous  excitability.  Warm  baths  have  been  used  for  convulsions 
of  infancy,  to  diminish  the  cerebral  manifestations  of  certain  acute  febrile 
disorders  and  to  treat  such  conditions  as  acute  sciatica,  dysmenorrhea, 
amenorrhea  and  insomnia.  Hot  baths  often  may  be  employed  to  advan- 
tage in  controlling  acute  exacerbations  of  chronic  atrophic  arthritis  as 
well  as  for  fibrositis,  myositis,  neuritis,  muscular  spasm  and  abdominal 
cramps.  Continuous  baths  are  used  particularly  in  the  control  of  acute 
manias.  They  have  been  employed  also  in  treatment  of  extensive  burns, 
indolent   ulcers,   cutaneous  diseases,    suppurating    wounds    and    large  ab- 

VoL.  I.  941 


CONTRAINDICATIONS  TO   HYDROTHERAPY     8io  (17) 

scesses.  Brine  baths  have  been  used  especially  for  arthritis,  fractures,  dis- 
locations, fibrositis,  myositis  and  osteomyelitis. 

Effervescent  baths  have  been  used  for  cardiac  disease,  especially  for 
valvular  or  myocardial  lesions.  The  oxygen  bath  has  been  recommended 
for  hypertension  and  cardiac  neurosis  and  as  a  mild  sedative  for  advanced 
cardiac  disease.  Bland  baths  are  used  to  relieve  generalized  pruritus  and 
dermatitis. 

Underwater  exercises  in  tanks  or  pools  are  employed  chiefly  for  pol- 
iomyelitis, spastic  paralysis  and  certain  orthopedic  and  neurological 
conditions.  Douches  and  showers  are  employed  to  improve  peripheral  cir- 
culation and  to  act  as  general  stimulants.  Neurasthenics  and  debili- 
tated individuals  often  are  benefited  by  the  Scotch  douche.  Packs 
can  be  used  to  advantage  in  home  treatment  of  arthritis,  fibrositis  or 
myositis  as  well  as  for  control  of  delirium,  psychosis,  hyperexcitability 
and  insomnia. 

Contraindications  to  the  Employment  of  Hydrotherapy 

Very  hot  or  very  cold  sitz  baths  should  not  be  administered  during 
pregnancy  or  the  menstrual  period.  Cold  local  baths  or  extremely  hot 
baths  at  a  temperature  higher  than  105°  F.  (40.6°  C.)  are  not  to  be  used 
in  the  presence  of  advanced  peripheral  vascular  disease.  The  former 
aggravate  the  condition,  and  the  latter  may  cause  burns,  which  would 
heal  slowly,  if  at  all. 

In  irrigation  of  the  nose  the  force  of  the  stream  must  not  be  too 
great,  or  else  infected  material  may  be  carried  into  the  eustachian  tube 
or  the  nasal  accessory  sinuses.  In  irrigating  the  throat,  if  the  stream  of 
fluid  is  directed  on  the  soft  palate  or  uvula,  it  may  cause  gagging.  Irriga- 
tion of  the  stomach  should  not  be  employed  to  remove  corrosive  poisons 
because  the  pressure  of  the  fluid  may  cause  perforation  of  the  eroded  wall 
of  the  stomach. 

Routine  daily  irrigations  of  the  vagina  are  potentially  harmful  be- 
cause they  may  remove  the  normally  germicidal,  vaginal  secretions. 
Colonic  irrigations  may  increase  rectal  discharges,  irritate  the  anus,  dis- 
turb a  chronic  ulcer  of  the  bowel,  produce  nausea  or  cause  fatal  intus- 
susception or  volvulus.  It  has  been  reported  that  they  may  cause  also 
rectal  bleeding,  from  hemorrhoids,  a  fissure  or  an  ulcer,  or  cause  a  torn 
rectal  valve.  In  one  instance  perforation  by  the  rectal  tube  of  a  diver- 
ticulum of  the  sigmoid  has  been  reported. 

Cold  compresses  should  not  be  used  in  the  presence  of  impaired  circu- 
lation,    sensitivity    to    cold    or    asthenia.      Hot    compresses    should    be 

Vol.  I.  941 


8io  (i8)  PHYSICAL   MEDICINE 

employed  with  caution  for  peripheral  vascular  disease  because  of  the  dan- 
ger of  burns  with  their  disastrous  consequences. 

General  cold  baths  should  not  be  used,  if  there  is  hypersensitivity  to 
cold,  because  collapse  may  occur.  Urticaria  also  may  be  produced  by 
cold  baths.  The  cold  bath  should  not  be  employed  in  the  presence  of 
arteriosclerosis,  nephritis,  spastic  paralysis,  nervous  irritability  or  cardiac 
weakness.  Neutral  baths  are  contraindicated,  if  the  patient  has  hypo- 
tension or  a  subnormal  bodily  temperature.  Hot  baths  are  not  to  be 
employed  in  the  presence  of  marked  hypertension,  advanced  debility, 
functional  neurosis  or  conditions  in  which  hemorrhage  impends. 

Among  the  dangers  of  continuous  baths  have  been  mentioned  heat 
prostration,  chilling,  scalding,  convulsions  and  drowning.  Continuous 
baths  should  not  be  employed  in  the  presence  of  cardiac  disease,  hypo- 
tension or  asthenia.  Carbon  dioxide  baths  should  not  be  used  for  patients 
who  have  marked  cardiac  decompensation,  congestive  heart  failure  or 
advanced  syphilitic  heart  disease. 

Underwater  exercises  are  contraindicated  for  acute  infections  or  febrile 
diseases,  acute  inflammations  of  joints,  acute  neuritis,  tuberculosis  of 
joints  and  during  the  acute  painful  stage  of  early  poliomyelitis.  General 
packs  should  not  be  employed  when  there  is  severe  circulatory  disturb- 
ance, advanced  cardiac  disease  or  extreme  exhaustion,  or  when  it  is 
evident  that  a  "reaction"  may  not  occur. 

Summary  of  Data  on  Hydrotherapy 

Many  local  and  general  hydrotherapeutic  procedures  are  simple  of 
application  and  can  be  employed  with  ease  in  the  patient's  home.  Physi- 
cians often  have  neglected  to  use  these  effective  procedures,  probably 
because  they  are  not  taught  properly  in  our  medical  schools. 

There  is  little  room  to  doubt  the  efficacy  of  contrast  baths,  whirlpool 
baths,  irrigations,  hot  tub  baths,  underwater  exercises  and  packs  in  the 
management  of  certain  pathological  conditions.  These  procedures  should 
be  employed  more  extensively  in  general  practice. 

BIBLIOGRAPHY  OF  HYDROTHERAPY 

1.  BARUCH,  S. :    An  Epitome  of  Hydrotherapy  for  Physicians,  Architects  and 

Nurses,  Saunders,  Philadelphia,   1920. 

2.  WOODMANSEY,  A.,  COLLINS,  D.  H.  and  ERNST,  M.  M.:   Vascular  reac- 

tions to  the  contrast  bath  in  health  and  in  rheumatoid  arthritis.  Lancet, 
1938,   II,    1350. 

3.  NYLIN,  J.   B.:    Hydrotherapy,    in   MOCK,  H.   E.,   PEMBERTON,   R.  and 
Vol.  I.  941 


BIBLIOGRAPHY  8io  (19) 

COULTER,  J.  S.,  Principles  and  Practice  of  Physical  Therapy,  Vol.   Ill, 
Chapt.  XX,  Prior,  Hagerstown,  Maryland,   1934. 

4.  BLAIR,  H.  C:    The  alternation  of  blood  supply  as  a  cause  for  normal  calcifi- 

cation of  bone,  Surg.,  Gynec.  and  Obst.,  1938,  LXVII,  413. 

5.  McCLELLAN,   W.  S.:    Hydrotherapy  and   balneotherapy.     In  BARR,  D.  P., 

Modern  Medical  Therapy  in  General  Practice,  Vol.    I,   pp.   711-750,  Wil- 
liams and  Wilkins,  Baltimore,  1940. 

6.  WRIGHT,  R. :    Hydrotherapy  in  Hospitals  for  Mental  Diseases,  Tudor  Press, 

Boston,  1932. 

Sept.  I,  1941. 


Vol.  I.  941 


8io  (20)  PHYSICAL   MEDICINE 

ELECTROTHERAPY 

The  types  of  electrical  current  commonly  employed  in  modern  medical 
practice  are  the  constant  current,  the  faradic  current,  the  various  sinus- 
oidal currents  and  the  high  frequency  or  diathermy  currents. 

The  Constant  Current 

The  constant  or  galvanic  current  is  a  unidirectional  current  of  low 
voltage  (tension)  and  amperage  (volume).  The  current  possesses  polarity, 
there  being  a  positive  and  a  negative  pole.  The  current  is  capable  of 
producing  migration  of  ions;  it  can  be  used  in  medicine  to  deposit  ions 
of  certain  salts  on  or  in  the  superficial  layers  of  the  skin  or  mucous  mem- 
branes. If  these  ions  are  concentrated  in  a  small  region,  destructive  chem- 
ical effects  of  a  caustic  nature  can  be  obtained. 

The  constant  current  is  employed  therapeutically  chiefly  for  electro- 
lysis, particularly  for  epilation,  and  for  common  ion  transfer,  iontopho- 
resis, of  a  few  medicinal  ions.  The  Council  on  Physical  Therapy  of  the 
American  Medical  Association^  has  said  that  the  interrupted  low  fre- 
quency current  and  the  constant  electric  current  "are  widely  used  in 
medical  practice  and  are  unquestionably  of  value  in  the  treatment  of  a 
limited  number  of  conditions". 

Methods  of  Applying  the  Constant  Current 

The  constant  current  can  be  derived  from  a  battery  of  electrical  cells, 
which  usually  are  connected  in  series  or  from  the  main  supply  current, 
if  this  is  of  the  direct  (D.  C.)  rather  than  of  the  alternating  (A.  C.)  va- 
riety. If  the  latter  is  used,  a  "shunt  resistance"  is  placed  in  the  patient's 
circuit  to  reduce  the  amount  of  current. 

In  the  United  States  the  house  current  usually  is  of  the  alternating 
(A.  C.)  variety;  this  can  be  employed  as  an  indirect  source  of  the  thera- 
peutic constant  current  only  by  the  introduction  of  a  motor  generator,  a 
rectifier  or  a  "B-battery  eliminator"  between  the  house  outlet  and  the 
patient. 

The  chief  advantages  of  a  therapeutic  device,  which  derives  its  con- 
stant current  from  a  battery  of  dry  cells,  are  that  it  is  portable  and  that 
it  is  not  dependent  on  any  outside  electrical  circuit.  The  specifications 
for  construction  of  a  simple,  low  cost,  constant  current  generator  have 
been  prepared  by  the  Council  on  Physical  Therapy  of  the  American 
Medical  Association  (Fig.  24). 

Vol.  I.  941 


THE   CONSTANT   CURRENT 


8io  (21) 


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GALVAMIC   UhlT 


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Contact 

Points 


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Fig.  24.  Specifications  for  the  construction  of  a  constant,  galvanic,  current  generator 
of  low  cost  (Courtesy  of  the  Council  on  Physical  Therapy  of  the  American  Medical 
Association). 


Vol.  I.  941 


8io  (22)  PHYSICAL   MEDICINE 

Physical  Principles  Concerned  in  the  Therapeutic  Application 
of  the  Constant  Current 

Certain  substances,  when  dissolved  in  water,  form  a  solution  that  pos- 
sesses an  osmotic  pressure  greater  than  that  of  water.  Such  a  solution 
will  conduct  a  constant  current.  The  molecules  are  decomposed  by  the 
current,  and  their  components  collect  at  either  the  positive  or  the  negative 
pole  of  the  current.  Acids,  bases  and  salts  are  included  among  the  sub- 
stances which  act  in  this  manner.  They  are  called  "electrolytes"  and 
the  smaller  particles  into  which  they  are  decomposed  are  called  "ions". 

When  the  constant  current  is  passed  through  an  aqueous  solution  of 
sodium  chloride,  a  migration  of  ions  will  occur.  Some  will  collect  at  the 
positive  and  others  at  the  negative  pole.  Similarly,  if  the  constant  cur- 
rent is  passed  through  the  bodily  tissues,  a  migration  and  a  concentration 
of  their  ions  will  occur  beneath  the  electrodes  connected  to  the  two  poles 
of  the  source  of  the  current.  The  therapeutic  effectiveness  of  the  con- 
stant current  depends  on  this  ability  to  cause  migration  of  ions. 

Action  and  Uses  of  the  Constant  Current 

When  applied  diffusely  to  the  skin,  the  constant  current,  because  of 
its  stimulating  effect  on  sensory  nerve  endings,  will  produce  reflex  vasodi- 
latation. However,  there  are  other  simpler  methods  of  obtaining  this 
effect. 

When  concentrated  at  the  tip  of  a  needle,  the  constant  current  will 
cause  chemical  changes,  owing  to  the  collection  of  ions,  which  are  so 
intense  that  caustic  effects  are  obtained.  Caustic  destruction  of  the 
tissues  ensues. 

The  ions  of  certain  metals  such  as  copper  or  zinc  and  of  certain  other 
substances  such  as  histamine  hydrochloride  and  mecholyl,  acetyl-beta- 
methylcholine  chloride,  have  been  introduced  into  the  superficial  layers 
of  the  skin  or  mucous  membranes  by  means  of  the  constant  current  for 
therapeutic  purposes. 

The  positive  pole  repels  metals  and  alkaloids  into  the  tissues;  the 
negative  pole  repels  acids,  acid  radicals  and  halogens.  This  should  be 
remembered,  when  attempts  are  made  to  introduce  these  substances  into 
the  tissues,  in  order  that  the  correct  pole  will  be  employed. 

When  iontophoresis  is  employed,  the  penetration  of  ions  never  will  be 

greater  than   a   fraction   of   a   millimeter;    nevertheless   certain   valuable 

superficial  effects  can  be  obtained.     The  low  velocity  of  the  ions  and  the 

low  potential,  at  which  they  are  introduced,  preclude  deep  penetration, 

Vol.  I.  941 


THE   CONSTANT   CURRENT  8io  (23) 

but  the  ions  can  be  absorbed  into  the  circulation  from  the  superficial 
layers  of  the  skin  and  thus  produce  distinct  local  and  even  systemic 
effects. 

Electrolysis  achieved  by  sharp  localization  of  caustic  products  at  the 
tip  of  a  needle  is  a  suitable  method  for  obtaining  destruction  of  certain 
lesions  of  the  skin  and  mucous  membranes.  The  indications  for  electro- 
lysis are  comparatively  few.  In  many  instances  the  newer  and  more 
readily  controlled  high  frequency  currents  are  used  for  destruction  of 
small  superficial  lesions.  There  are,  however,  several  conditions  for  which 
electrolysis  still  is  considered  the  method  of  choice.  Both  MacKee^  and 
Cipollaro'  recom.mended  electrolysis  for  destruction  of  certain  cutaneous 
lesions,  such  as  adenoma  sebaceum,  dilated  capillaries,  benign  cystic 
epitheliomas,  hemangiomas,  hydrocystomas,  hypertrichosis,  keratosis,  pig- 
mented hairy  moles,  spider  nevi  and  syringocystadenomas.  By  far  the 
most  common  and  important  indication  for  electrolysis  is  hypertrichosis. 
As  Cipollaro^  stated:  "It  is  the  only  method  for  permanent  and  safe 
removal  of  unwanted  hairs." 

For  selected  cases  of  chronic  otorrhea  Friel*  has  recommended  the  em- 
ployment of  zinc  iontophoresis.  Lierle  and  Sage^  were  not  impressed  so 
favorably  with  the  procedure,  and  Hollender^  concluded  that,  although 
the  method  may  be  useful  in  selected  cases,  the  evidence  presented  to 
date  is  insufficient  to  place  the  procedure  on  a  firm  scientific  basis.  Re- 
cently zinc  iontophoresis  has  been  recommended  in  treatment  of  hay  fever 
and  rhinitis.  The  method  may  cause  fibrosis  of  the  nasal  submucosa 
without  damage  to  the  superficial  epithelium.  Local  application  of  phenol 
can  produce  a  similar  effect.  At  best  the  procedure  is  palliative  and  not 
curative.  It  has  seemed  to  be  more  effective  in  non-allergic  rhinitis  than 
in  seasonal  hay  fever.  Its  value  and  dangers  as  yet  have  not  been  de- 
termined fully. 

Kovacs'^  has  recommended  the  employment  of  iontophoresis  of  mecholyl, 
acetyl-beta-methylcholine  chloride,  in  treatment  of  varicose  ulcers.  Zinc 
or  copper  iontophoresis  has  been  employed  in  the  past  for  indolent  ulcers. 

Kling*  advocated  the  use  of  histamine  iontophoresis  in  treatment  of 
peripheral  circulatory  diseases.  He  was  of  the  opinion  that  the  procedure 
was  more  effective  than  were  inunctions  of  histamine.  Neither  procedure 
is  particularly  effective  in  peripheral  vascular  diseases.  I  have  tried 
histamine  iontophoresis  and  could  see  no  advantage  over  other  simpler 
methods  of  producing  hyperemia. 

Several  authors^-  ^'  ^°'  ^^  have  urged  strongly  the  use  of  iontophoresis  of 
histamine  or  of  mecholyl  (acetyl-beta-methylcholine  chloride)  in  treatment 
of  atrophic,  hypertrophic  or  traumatic   arthritis.      It  was  thought  that 

Vol.  I.  941 


8io  (24)  PHYSICAL   MEDICINE 

the  procedure  caused  local  vasodilatation  within  the  joint  over  which  it 
was  applied.  It  has  been  commented  that  this  can  be  "little  more  than 
pure  conjecture".  I  have  found  little  to  recommend  the  procedure  and 
prefer  simpler  methods  of  producing  vasodilatation  in  treatment  for 
arthritis. 

Copper  iontophoresis  has  been  employed  for  many  years  in  treatment 
for  endocervicitis,  but  no  one  seems  to  have  compared  it  carefully  with 
other  methods  of  treatment.  Tovey'^,  for  example,  recommended  the 
procedure  enthusiastically  but  presented  no  statistical  or  comparative 
studies  to  support  his  views. 

Contraindications  to  the  Employment  of  the  Constant  Current 

Following  iontophoresis  of  either  histamine  or  mecholyl  (acetyl-beta- 
methylcholine  chloride)  untoward  systemic  reactions  may  occur  which 
must  be  guarded  against.  When  electrolysis  is  performed,  care  should 
be  taken  to  avoid  application  of  the  current  from  the  positive  pole  through 
a  steel  needle,  or  else  a  tattoo  may  result.  Incorrect  technic  in  electrol- 
ysis may  cause  painful,  disfiguring  or  even  dangerous  lesions.  Infections, 
keloids  or  regions  of  depigmentation  may  occur.  Incomplete  destruction 
of  a  benign  melanoma  may  cause  it  to  become  malignant. 

Use  of  excessive  amounts  of  current  in  copper  iontophoresis  of  the 
cervix  may  produce  sloughing  and  subsequent  stenosis  of  the  cervical 
canal.  Improper  employment  of  zinc  iontophoresis  in  the  nose  may 
result  in  impairment  of  the  sense  of  smell. 

Summary  of  Data  on  the  Constant  Current 

The  constant  current  is  useful  chiefly  for  electrolysis  and  for  ionto- 
phoresis. Electrolysis  is  indispensable  for  safe  epilation  and  can  be  em- 
ployed to  advantage  also  for  destruction  of  a  few  cutaneous  lesions. 

Iontophoresis  of  certain  medicinal  ions  may  be  employed  occasionally 
for  therapeutic  purposes.  The  constant  current  has  a  distinct  but  limited 
field  of  usefulness  in  medicine. 

The  Faradic  Current 

The  therapeutic  use  of  the  faradic  current  followed  the  discovery  by 
Michael  Faraday  in  1831  of  electromagnetic  induction.  Guillaume  Du- 
chenne  is  believed  to  have  been  the  first  to  employ  the  faradic  current  in 
medicine.     He  thought  that  faradic  stimulation  aided  in  the  recovery  of 

Vol.  I.  941 


THE   FARADIC   CURRENT  8io  (25) 

weakened  muscles  by  increasing  their  circulation.  He  was  sufficiently 
observant  to  realize,  however,  that  the  procedure  was  not  so  effective  in 
strengthening  weakened  muscles  as  was  voluntary  contraction. 

The  faradic  current,  which  is  employed  for  therapeutic  purposes,  is  an 
intermittent,  asymmetrical,  alternating  current  obtained  from  the  secon- 
dary winding  of  an  induction  coil.  Like  the  constant  current  its  field  of 
usefulness  is  distinctly  limited.  At  present  it  is  employed  chiefly  for 
stimulation  of  weak  or  atrophied  muscles,  which  have  a  normal  nerve 
supply,  for  testing  for  the  reaction  of  degeneration  and  as  a  means  of 
suggestion  for  treatment  of  hysteria. 

Methods  of  Applying  the  Faradic  Current 

Small  faradic  units  long  have  been  marketed  for  medical  use.  Any 
electrician  can  build  one  at  small  cost  by  following  the  directions  which 
have  been  prepared  by  the  Council  on  Physical  Therapy  of  the  American 
Medical  Association  (Fig.  25). 

This  device  employs  a  sliding  iron  core  which  permits  the  current  in 
the  secondary  coil  to  be  varied  smoothly  in  a  surging  manner.  This 
surging  of  the  current  by  sliding  the  core  in  and  out  permits  the  operator 
to  produce  rhythmic  graduated  contractions  of  muscles  through  which 
the  current  is  passed. 

More  elaborate  types  of  the  faradic  unit  dispense  with  the  manual 
production  of  variation  in  the  current  and  employ  motor  driven  cams  or 
other  mechanisms  to  vary  its  intensity.  A  suitable  portable  faradic  coil, 
which  has  been  employed  extensively  in  England,  has  been  developed  by 
Sir  Morton  Smart^^'  ^\ 

Physical  Principles  Concerned  in  the  Therapeutic  Application 
of  the  Faradic  Current 

The  device  for  production  of  a  faradic  current  consists  of  a  constant 
current  source  such  as  a  battery  of  electrical  cells,  an  induction  coil  and  a 
current  interrupter.  The  primary  coil  of  the  apparatus  consists  of  a  few 
turns  of  copper  which  encircle  a  core  made  of  a  bundle  of  soft  iron  wires. 
The  secondary  coil  consists  of  many  turns  of  fine  copper  wire  which  en- 
circle a  hollow  fiber  cylinder.  This  cylinder  is  made  to  ensheathe  the 
primary  coil.  Either  this  cylinder  or  the  iron  core  is  arranged  so  that  it 
can  be  slid  in  or  out  to  vary  the  amount  of  induced  current  in  the  secon- 
dary coil. 

The  asymmetrical  current,  which  flows  from  the  secondary  coil,  will 

Vol.  I.  941 


8io  (26) 


PHYSICAL   MEDICINE 


HOMEMADE  PARADIC    COIL  FOIL  CrlUDUATED    MUSCLE    STIMULATION 


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Fig.  25.    Specifications  for  the  construction  of  a  simple  faradic  coil  (Courtesy  of  the 
Council  on  Physical  Therapy  of  the  American  Medical  Association). 

Stimulate   contractions   of   normal    muscles   but   will   not   cause   muscles, 
which  have  lost  their  nerve  supply,  to  contract. 
Vol.  I.  941 


THE   FARADIC   CURRENT  8io  {2^) 

Action  and  Uses  of  the  Faradic  Current 

The  physiological  efifect  of  faradic  stimulation  of  muscles  is  similar 
to  that  of  other  forms  of  electrical  stimulation.  However,  the  method  of 
accomplishing  the  muscular  contraction  differs  from  that  of  other  currents. 

The  effective  phase  of  the  secondary  faradic  current  occurs  at  the 
"break".  These  "break"  phases  occur  at  a  rate  of  50  to  100  times  per 
second.  These  "break"  stimuli  follow  one  another  so  rapidly  that  the 
muscle,  which  possesses  a  normal  nerve  supply,  will  have  no  time  to  relax 
between  stimuli,  and  a  smooth  even  tetanus  will  result.  The  very  short 
"break"  stimuli,  lasting  o.ooi  second,  although  very  suitable  for  stimu- 
lating the  normal  muscle,  which  has  a  chronaxia  of  0.0015  second,  will 
not  produce  any  effect  on  a  paralyzed  muscle  which,  because  of  its  lack 
of  innervation,  has  a  chronaxia  of  o.oi  to  O.i  second. 

These  facts  form  the  basis  for  the  employment  of  the  faradic  current 
in  testing  for  reaction  of  degeneration.  A  muscle  with  an  intact  normal 
nerve  supply  will  respond  to  faradic  stimulation,  whereas  if  the  nerve 
supply  is  damaged  or  degenerated,  the  muscle  will  not  respond.  The 
details  of  the  test  for  reaction  of  degeneration  will  not  be  described  here 
but  can  be  found  in  other  books'*-  ^^. 

As  has  been  mentioned,  the  faradic  current  is  employed  chiefly  for 
performing  this  test  or  for  stimulation  of  muscles  which  have  poor  tone 
but  possess  a  normal  nerve  supply.  It  is  particularly  useful  in  stimulating 
muscles  which  have  lost  tone  and  have  become  atrophied  following  pro- 
longed disuse.  The  current  also  can  be  applied  by  means  of  a  special 
brush  electrode  to  cause  strong,  painful,  muscular  contractions  as  a  means 
of  inducing  suggestion  in  cases  of  hysteria.  Another  valuable  application 
of  the  faradic  current  is  for  the  purpose  of  teaching  a  patient  to  contract 
one  muscle  independently.  Muscle  setting  exercises  often  are  valuable, 
but  it  may  be  difficult  to  train  a  patient  to  contract  the  correct  muscle 
or  muscles.  Faradic  stimulation  of  the  muscles  in  question  immediately 
will  demonstrate  to  the  patient  which  muscles  are  to  be  contracted.  Once 
he  feels  these  muscles  contract,  he  may  be  able  to  continue  the  con- 
tractions voluntarily.  The  electrical  stimulation  may  save  several  hours 
of  explanation  and  practice. 

Faradic  stimulation  occasionally  can  be  employed  to  produce  rhythmic 
contractions  of  muscles  which  the  patient  cannot  or  will  not  contract  of 
his  own  volition.  Smart^^-  '*  recommended  its  employment  for  many 
conditions  including  such  as  strains,  muscular  atrophy,  fibrositis,  teno- 
synovitis, sprains,  dislocations,  fractures,  arthritis  and  certain  forms  of 
paralysis. 

Vol.  I.  941 


8io  (28)  PHYSICAL   MEDICINE 

Contraindications  to  the  Use  of  the  Faradic  Current 

Faradic  stimulation  is  contraindicated  in  treatment  during  the  acute 
stage  of  sprains  in  which  the  muscular  contractions,  which  it  produces, 
might  cause  further  extravasation  of  blood  and  lymph  into  the  tissue 
spaces  and  might  interfere  with  normal  repair.  Stimulation  of  muscles 
by  the  faradic  current  should  be  used  with  caution  in  recent  fractures 
because  of  the  danger  of  disturbing  the  alignment  of  the  fragments.  It 
should  be  remembered  that  voluntary  exercises  are  to  be  preferred  to 
faradic  stimulation  of  the  muscles. 

Summary  of  Data  on  the  Faradic  Current 

As  with  other  low  voltage  therapeutic  currents  the  faradic  current  has 
a  small  but  definite  field  of  usefulness.  The  current  is  derived  from  a 
fairly  simple  apparatus  and  is  easy  to  apply.  It  is  indispensable  for  use 
in  performance  of  the  test  for  reaction  of  degeneration  and  is  valuable 
for  stimulating  weak  and  atrophied  muscles. 

The  Interrupted  Galvanic  and  Sinusoidal  Currents 

The  interrupted  or  waved  currents  of  this  group  are  of  low  voltage  and 
amperage.  The  group  includes  the  interrupted  galvanic  current,  the  slow 
sinusoidal  current  and  the  rapid  sinusoidal  current.  There  are  numerous 
modifications  of  these  basic  forms  of  current,  for  which  a  uniform  nomen- 
clature has  not  been  determined. 

The  interrupted  galvanic  current  is  a  unidirectional  current  which  is 
made  and  broken,  turned  on  and  off,  sharply.  When  passed  through 
normal  muscles,  it  will  produce  quick,  brief,  muscular  contractions  at 
each  make  and  break  of  the  current.  The  slow  sinusoidal  current  is  an 
alternating  current,  the  volume  of  which  can  be  represented  as  traveling 
in  the  course  of  a  sinusoid.  In  other  words  a  graph  of  the  current  volume 
looks  like  a  series  of  symmetrical  waves.  The  potential  rises  slowly  from 
zero  to  maximum,  then  gradually  returns  to  zero;  it  then  reverses  and 
repeats  this  action.  The  rate  of  alternation  usually  is  5  to  30  per  minute. 
Smooth  muscles  and  skeletal  muscles,  which  are  in  a  state  of  flaccid 
paralysis,  usually  will  respond  to  this  current. 

The  rapid  sinusoidal  current  is  similar  to  the  slow  sinusoidal  current 
with  the  exception  that  its  rate  of  oscillation  is  much  greater,  the  rate 
being  120  alternations,  60  cycles,  or  more  per  second.  The  rapid,  sinus- 
oidal current  alternates  so  rapidly  that,   although   it  will  cause  smooth 

Vol.  I.  941 


GALVANIC   AND   SINUSOIDAL   CURRENTS       8io  (29) 

tetanization  of  normal  skeletal  muscles,  no  single  stimulus  is  long  enough 
to  produce  a  contraction  in  a  paralyzed  muscle. 

Modifications  of  these  basic  interrupted  or  waved  currents  include 
various  types  of  surging,  such  as  the  types  known  as  the  surging  sinusoidal 
current  and  the  surging  sinusoidal  current  with  a  sustained  peak. 

When  employed  for  stimulation  of  muscles,  the  sinusoidal  currents  are 
somewhat  less  unpleasant  than  is  the  faradic  current  because  their  alter- 
nations are  perfectly  smooth.  The  indications  for  their  use  are  practically 
the  same  as  those  for  the  faradic  current. 

Methods  of  Applying  the  Interrupted  Galvanic  and  Sinusoidal  Currents 

The  interrupted  galvanic  current  is  produced  by  the  apparatus  for 
generation  of  the  constant,  galvanic  current  with  the  exception  that  some 
method  must  be  provided  for  making  and  breaking  the  electrical  circuit. 
A  make  and  break  key  or  button  can  be  used  to  permit  manual  inter- 
ruption of  the  current,  or  some  mechanical  interrupter  such  as  a  metro- 
nome, rotating  cam  or  automatic  switch  can  be  employed. 

To  obtain  the  slow  sinusoidal  current  a  source  of  galvanic  current  can 
be  employed  in  conjunction  with  a  variable  resistance  and  current  re- 
verser  which  will  wave  the  current  in  the  form  of  a  sinusoid.  The  rapid 
sinusoidal  current  usually  is  derived  from  an  alternating  current  main 
and  is  modified  and  protected  suitably.  Elaborate  machines,  which  pro- 
duce the  three  basic  currents  variously  modified,  have  been  marketed. 

Physical  Principles  Concerned  in  the  Application  of  the  Interrupted 
Galvanic  and  Sinusoidal  Currents 

The  physics  of  the  interrupted  galvanic  current  is  the  same  as  that  of 
the  constant  current.  The  ordinary  house  current  usually  is  a  rapid 
sinusoidal  current  of  60  cycles  and  of  such  high  voltage  and  amperage 
that,  unmodified,  it  cannot  be  employed  for  therapeutic  purposes.  If 
the  voltage  and  amperage  are  reduced  to  tolerable  volumes,  then  the 
current  can  be  employed  for  stimulation  of  muscles  possessing  a  normal 
nerve  supply. 

No  rate  of  oscillation  ever  has  been  agreed  on  as  the  dividing  line 
between  rapid  and  slow  sinusoidal  currents.  It  has  been  suggested  that, 
if  no  single  wave  before  reversal  of  flow  lasts  longer  than  1/50  (0.02)  of 
a  second,  such  a  sinusoidal  current  should  be  called  "rapid";  that  if  the 
length  of  time  for  the  completion  of  one  wave  is  greater  than  1/50  (0.02)  of 
a  second,  then  the  current  can  be  considered  to  be  a  slow  sinusoidal  current. 

Vol.  I.  941 


8io  (30)  PHYSICAL   MEDICINE 

Usually  with  the  rapid  sinusoidal  current  the  duration  of  the  period 
of  flow  before  reversal  will  be  from  1/50  (0.02)  to  1/200  (0.005)  of  a  second. 
With  the  current  of  60  cycles  the  duration  would  be  1/120  (0.008)  of  a 
second  because  there  are  120  alternations  to  60  cycles. 

Action  and  Uses  of  the  Interrupted  Galvanic  and  Sinusoidal  Currents 

When  these  interrupted  or  waved  currents  are  passed  through  human 
tissues,  the  electrochemical  changes,  which  are  produced,  may  stimulate 
nerves  or  cause  muscles  to  contract.  The  action  has  been  attributed  to 
concentration  of  hydrogen  or  hydroxyl  ions. 

The  contractions  caused  by  the  interrupted  galvanic  current  are  sepa- 
rate and  brief;  hence,  they  do  not  resemble  normal  muscular  contractions. 
Voluntary  muscular  contractions  are  more  prolonged  and  result  from  a 
series  of  nerve  stimuli,  which  are  said  to  occur  at  the  rate  of  more  than 
twenty  per  second.  Therefore,  the  interrupted  galvanic  current  is  not 
the  most  suitable  current  for  therapeutic  use,  and  it  is  employed  only  for 
stimulation  of  weak,  paralyzed  muscles,  which  will  not  respond  to  the 
waved  currents.  There  has  been  a  great  deal  of  controversy  concerning 
the  role  of  electrical  stimulation  in  treatment  for  various  types  of  lesions 
of  the  lower  motor  neurons  with  resultant  paralysis.  Some  physicians^^-  ^^ 
contend  that  electrical  stimulation  will  maintain  contractility,  irritability, 
tone  and  nutrition  until  such  time  as  regeneration  of  the  nerve  takes  place, 
if  it  takes  place  at  all.  Others^^-  ^°  are  equally  positive  that  electrical 
stimulation  has  no  place  whatever  in  the  treatment  of  paralysis  and  may 
do  much  harm. 

Because  of  this  controversy  the  comparatively  recent  studies  of 
Fischer^^  are  significant.  He  noted  that  in  spite  of  this  prolonged  clinical 
dispute  concerning  the  value  of  electrotherapy  in  treating  paralyzed 
muscles,  almost  no  experimental  data  could  be  found  to  support  the 
contention  of  either  group.  He  performed  tests  on  laboratory  animals 
with  either  a  tetanizing  faradic  current  from  an  induction  coil  or  an  in- 
terrupted galvanic  current  from  dry  cells.  After  extensive  study  and  ex- 
perimentation he  reached  a  number  of  interesting  conclusions.  Among 
these  were  the  following:  If  a  denervated  muscle  has  been  left  untreated 
for  about  two  weeks  or  more,  faradic  stimulation  no  longer  produces  an 
appreciable  contraction.  In  such  instances  galvanic  stimulation  will 
provoke  contractions,  and  repeated  daily  treatments  will  delay  the 
lengthening  of  chronaxia  to  some  extent  but  not  nearly  so  markedly  as 
will  early  treatment  by  faradic  current.  The  fact  that  electrical  treat- 
ment of  muscles  decreases  the  rate,  previously  increased  by  denervation, 

Vol.  I.  941 


GALVANIC   AND   SINUSOIDAL   CURRENTS       8io  (31) 

at  which  weight  and  water  content  are  lost  and  also  increases  "the 
quantitatively  raised,  but  qualitatively  impaired,  metabolism"  seems  to 
afford  a  clue  for  the  explanation  of  the  beneficial  effect  of  the  treatment. 
This  effect  is  identical  with  the  training  effect  on  normal  muscle  produced 
by  electrical  stimulation.  In  normal  muscles,  also,  the  weight  increases, 
and  the  metabolism  is  raised  and  increased  in  efficiency  by  strong  electrical 
stimulation.  A  treated  muscle  five  weeks  after  denervation  has  about  the 
same  weight  as  an  untreated  muscle  about  one  week  after  denervation. 
The  power  of  a  muscle  treated  for  five  weeks  is  appreciably  greater  than 
that  of  its  untreated  partner.  It  is  noted  especially  that  the  treated 
muscle  is  less  fatigable.  Despite  remarkable  retardation  of  loss  of  weight 
and  diminished  loss  of  dry  substance,  the  treatment  has  failed  to  improve 
the  contractile  mechanism.  But  after  reinnervation  it  seems  reasonable 
to  assume  that  a  treated  muscle  with  its  higher  excitability,  its  greater 
weight,  its  lower  content  of  water  and  its  increased  metabolism  could  be 
restored  more  easily  to  normal  function  than  an  untreated  muscle.  These 
studies  seem  significant  and  would  seem  definitely  to  refute  the  claims  of 
those  who  say  that  electrical  stimulation  plays  no  part  in  the  treatment 
of  paralyzed  muscles. 

The  uses  of  the  interrupted  galvanic  current  in  medicine  are  few. 
It,  of  course,  is  employed  routinely  in  conjunction  with  the  faradic 
current  in  performance  of  the  test  for  reaction  of  degeneration.  It  is 
used  occasionally  also  for  stimulation  of  extremely  weak,  paralyzed  mus- 
cles which  will  not  respond  to  the  slow  sinusoidal  or  to  other  waved  gal- 
vanic currents. 

The  slow  sinusoidal  current  is  used  for  stimulation  of  unstriped  muscles 
and  sometimes  can  be  used  to  produce  contractions  of  paralyzed  skeletal 
muscles.  The  rapid  sinusoidal  current  is  employed  for  stimulation  of 
weak  or  atrophied  muscles  which  have  a  normal  nerve  supply.  For  this 
purpose  it  is  somewhat  less  unpleasant  than  the  faradic  current. 

Not  only  have  the  interrupted  galvanic  and  slow  sinusoidal  currents 
been  employed  in  treatment  for  lesions  of  the  lower  motor  neurons,  but 
their  use  has  been  suggested^  also  for  lesions  of  the  upper  motor  neurons 
such  as  hemiplegia  or  myelitis.  Electrical  stimulation  has  been  employed 
for  prevention  of  atrophy  of  the  quadriceps  or  deltoid  muscle  following 
injury  to  the  knee  or  shoulder,  to  improve  muscular  tone  in  cardiovascular 
disorders  and  to  initiate  respiration  in  asphyxia  of  the  newborn. 

The  rapid  sinusoidal  current  can  be  used  interchangeably  with  the 
faradic  current.  Therefore,  the  indications  listed  under  Action  and  Uses 
of  the  Faradic  Current  can  be  consulted  for  further  information  concern- 
ing possible  uses  of  the  rapid  sinusoidal  current. 

Vol.  I.  941 


8io  (32)  PHYSICAL   MEDICINE 

Contraindications  to  the  Application  of  the  Interrupted  Galvanic 
and  Sinusoidal  Currents 

Electrical  stimulation  is  contraindicated  in  cerebrospastic  paralysis, 
combined  sclerosis  of  the  spinal  cord,  progressive  muscular  atrophy  and 
myasthenia  gravis.  In  stimulation  of  paralyzed  muscles  excessive  treat- 
ment may  produce  fatigue  and  do  more  harm  than  good.  Such  stimula- 
tion always  should  be  applied  within  limits  of  fatigue.  If  there  is  slowing 
of  muscular  response,  which  is  the  first  sign  of  fatigue,  treatment  should 
be  stopped  at  once. 

It  has  been  said  that,  if  alternating  or  sinusoidal  currents  are  applied 
to  the  cardiac  region,  they  may  cause  cardiac  fibrillation.  It  must  be 
stressed  once  more  that  electrical  stimulation  always  is  less  valuable  than 
is  voluntary  exercise. 

Summary  of  Data  on  the  Interrupted  Galvanic  and  Sinusoidal  Currents 

A  few  simple  modifications  of  the  three  basic  currents,  which  have 
been  discussed,  are  all  that  is  necessary  for  satisfactory  electrical  stimu- 
lation of  muscles.  Elaborate  apparatus  is  not  required  for  this  purpose. 
The  simpler  devices  are  entirely  satisfactory  for  production  of  muscular 
contractions.     There  are  several  uses  for  such  apparatus. 

Diathermy 

By  far  the  most  valuable  form  of  electrical  current  for  use  in  medicine 
and  surgery  is  the  high  frequency,  or  diathermy,  current.  It  has  been 
found  that,  if  an  electrical  current  is  made  to  oscillate  at  an  extremely 
rapid  rate,  it  can  be  passed  through  the  tissues  of  the  human  body  with- 
out producing  any  neuromuscular  response;  hence  no  electrical  "shock" 
is  produced.  Under  such  circumstances  both  the  voltage  and  the  am- 
perage of  the  current  can  be  increased  so  that  an  increase  in  temperature 
will  develop  in  the  tissues  traversed  by  the  current. 

In  this  manner  a  means  of  producing  deep  local  heating  of  bodily 
tissues  is  obtained  without  any  other  effects  on  these  tissues.  To  employ 
a  crude  analogy,  just  as  the  filament  of  an  ordinary  electric  light  bulb 
glows  to  white  heat  owing  to  the  resistance  it  offers  to  the  flow  of  a  60 
cycle  current  of  relatively  high  voltage,  so  to  a  lesser  degree  will  the 
bodily  tissues  become  heated  owing  to  the  resistance  which  they  ofifer 
to  the  flow  of  this  current  of  relatively  high  voltage  and  very  high  fre- 
quency.    The  patient  would  receive  a  severe  electrical  shock  from  a  60 

Vol.  I.  941 


DIATHERMY 


8io  (33) 


Fig.  26.    A  conventional  diathermy  machine  (From  Krusen,  F.  H.:    Physical  Medi- 
cine, Saunders,  Philadelphia,  1941). 


Vol.  I.  941 


8io  (34)  PHYSICAL   MEDICINE 

cycle  current  of  sufficient  voltage  and  amperage  to  heat  the  tissues,  but 
he  receives  no  such  shock  from  the  current  of  high  frequency. 

Because  of  the  heating  of  the  tissues  which  are  traversed  by  the  cur- 
rent, the  procedure  has  been  called  "diathermy".  This  designation  has 
become  well  established  as  the  proper  term  for  the  description  of  the 
application  of  high  frequency  currents  of  relatively  long  wavelengths, 
500,000  to  3,000,000  cycles  per  second. 

Following  the  development  of  the  triode  principle  of  electronic  oscil- 
lations, radio  engineers  were  able  to  construct  excellent  vacuum  tube 
oscillators  which  would  produce  currents  of  much  higher  frequencies,  and 
shorter  wavelengths,  than  previously  had  been  employed.  The  newer 
machines,  which  employed  vacuum  tubes,  were  able  to  produce  an  oscil- 
lating current  of  extremely  high  frequency,  from  10,000,000  cycles  per 
second  and  a  30  meter  wavelength  to  100,000,000  cycles  per  second  and  a 
3  meter  wavelength. 

With  the  development  of  these  new  machines  it  has  become  the 
custom  in  the  United  States  to  call  longer  wavelength  machines  "conven- 
tional diathermy"  apparatus  and  the  new  shorter  wavelength  devices 
"short  wave  diathermy"  machines.  In  Europe  the  much  less  explicit  and 
less  descriptive  designation  "short  wave  therapy"  still  is  employed  fre- 
quently. 

Methods  of  Applying  Diathermy 

A  typical  apparatus  for  producing  conventional  diathermy  consists  of 
(r)  a  source  of  alternating,  60  cycle,  current,  (2)  a  switch,  (3)  a  choke 
coil,  current  intensity  regulator,  (4)  a  step-up  transformer,  (5)  spark 
gaps,  (6)  condensers,  (7)  a  solenoid  and  (8)  an  inductor  (Fig.  26).  Such 
an  arrangement  delivers  a  moderately  high  frequency  current  to  a  patient. 
Wires  leading  from  the  machine  to  metal  plates  on  the  surface  of  the 
patient's  body  will  provide  a  conductive  type  of  high  frequency  current 
for  passage  through  the  body.  With  the  development  of  the  newer 
short  wave  diathermy  machine  the  older  conventional  diathermy  appara- 
tus largely  has  been  discarded.  Nevertheless  it  still  is  useful  and  some- 
times can  be  employed  to  better  advantage  than  the  newer  machine  for 
localizing  heat  in  a  small  region. 

The  most  common  type  of  apparatus  for  production  of  short  wave 
diathermy  current  consists  of  a  simple  two  tube,  "push-pull"  circuit 
(Fig.  27).  The  circuit  consists  of  three  essential  parts;  (i)  the  power 
supply,  (2)  the  oscillating  circuit  and  (3)  the  output  circuit.  For  further 
details,  the  reader  can  consult  an  article  by  Hemingway  and  Stenstrom^^ 

Vol.  I.  941 


DIATHERMY 


8io  (35) 


in  which  the  circuits  are  well  described.  The  appliance  for  the  production 
of  short  wave  diathermy  resembles  in  construction  a  short  wave  radio 
transmitter  with  the  exception  that  the  electrical  energy,  instead  of  being 
dispersed  from  antennas  as  in  broadcasting,  is  confined  mostly  between 


Fig.  27.  A  short  wave  diathermy  machine  (From  Krusen,  F.  H.:  Physical  Medi- 
cine,  Saunders,   Philadelphia,   1941). 

condenser  plates  to  produce  an  electrical  field  or  is  confined  within  a  coil 
to  produce  an  electromagnetic  field. 

Human  tissues,  acting  partly  as  conductors  and  partly  as  dielectrics, 
when  placed  within  these  fields,  presumably  are  heated  by  the  production 
of  ionic  oscillations  and  molecular  friction.  Power  losses  occur,  and  heat- 
ing of  the  deep  tissues  is  produced. 

Vol.  I,  941 


8io  (36)  PHYSICAL   MEDICINE 

Physical  Principles  Concerned  in  the  Application  of  Diathermy 

With  regard  to  the  position  of  electrodes  with  conventional  diathermy 
it  is  necessary  to  have  the  electrodes  in  direct  contact  with  the  skin  or 
the  mucous  membranes.  This  may  be  unsatisfactory,  especially  if  a  large 
electrode  is  to  be  used  over  an  irregular  surface.  However,  if  short  wave 
diathermy  is  to  be  employed,  an  insulating  pad  or  layer  of  air  can  be 
interposed  between  the  electrode  and  the  surface  of  the  body.  Thus, 
by  applying  short  wave  diathermy  electrodes  at  a  distance  from  the  sur- 
face, it  is  possible  to  heat  a  deeper  region  of  the  body  without  undue 
heating  of  the  skin. 

Selective  Heating.  —  It  has  been  claimed  that  the  newer  short  wave 
diathermy  currents  will  produce  "selective  heating"  of  various  bodily 
tissues;  that  is,  because  different  tissues  have  different  dielectric  constants, 
they  will  be  heated  to  a  greater  or  lesser  degree.  Basing  their  claims  on 
this  therapeutic  conception,  a  number  of  enthusiasts  have  concluded  that 
it  would  be  possible,  therefore,  to  heat  one  organ  of  the  body  to  a  greater 
degree  than  another.  Although  it  is  true  that  short  wave  diathermy  will 
produce  selective  heating  of  inorganic  substances  and  of  dead  tissues,  it 
now  has  been  demonstrated  repeatedly  that  in  the  living  animal,  owing  to 
dissipation  of  heat  by  the  circulation,  no  such  selective  heating  of  tissues 
can  be  expected. 

Thermopenetration.  —  For  various  physical  reasons  it  is  evident  that 
short  wave  diathermy  should  produce  more  uniform  and  deeper  penetra- 
tion of  heat  than  does  conventional  diathermy.  As  yet,  despite  a  number 
of  investigations  of  the  problem,  there  is  no  conclusive  proof  of  this. 
Further  observations  eventually  may  indicate  the  comparative  thermo- 
penetration of  these  two  forms  of  diathermy. 

Dosage.  —  At  present  there  is  no  means  for  accurate  determination  of 
the  dosage  of  short  wave  diathermy.  Watt  meters  are  being  developed 
which  may  help  to  give  some  indication  of  proper  dosage;  however,  these 
are  not  entirely  accurate.  At  present  the  physician,  who  applies  short 
wave  diathermy,  must  rely  on  his  careful  observation  of  the  sensation 
of  heat  felt  by  the  patient  and  from  this  must  govern  the  dosage  as  accu- 
rately as  possible.  Because  of  this  need  for  careful  observation  of  the 
sensations  of  the  patient  by  a  skilled  physician  or  technician  no  patient 
ever  should  be  permitted  to  control  the  dials  of  the  apparatus  himself. 

Wavelength.  —  It  has  been  claimed  by  various  investigators  that  dif- 
ferent wavelengths  produce  different  effects  on  the  bodily  tissues;  how- 
ever, as  more  and  more  experimental  evidence  is  amassed,  it  becomes 
evident  that  the  only  effect  of  short  wave  diathermy  on  the  bodily  tissue 

Vol.  I.  941 


DIATHERMY  8io  (37) 

is  a  thermal  one,  and  that  within  the  range  between  3  and  30  meters  one 
wavelength  has  no  particular  advantage  over  another. 

Actioji  and   Uses  of  Diathermy 

It  has  been  demonstrated  that  appreciable  rises  in  temperature  of 
more  than  5°  F.  or  of  2.75°  C.  can  be  obtained  at  a  depth  in  comparatively 
avascular  tissues.  If  the  tissues  are  highly  vascular,  little  increase  in 
temperature,  not  more  than  0.9°  F.  or  0.5°  C,  will  be  found.  It  fre- 
quently has  been  claimed  by  enthusiasts  that  short  wave  diathermy  will 
produce  certain  physiological  effects  other  than  those  attributable  to 
heating,  but  a  large  amount  of  experimental  data  now  has  been  amassed, 
which  seems  definitely  to  indicate  that  no  specific  physiological  efifects 
other  than  those  attributable  to  heating  exist. 

The  numerous  scientific  investigations  of  the  effect  of  diathermy  on 
bacteria  now  permit  the  conclusion  that  neither  in  vitro  nor  in  vivo  are 
there  specific  bactericidal  efifects  other  than  those  attributable  to  heat. 

Whereas  high  frequency  currents  may  be  employed  to  great  advantage 
for  electrosurgery,  fulguration,  desiccation,  coagulation  and  electric  cut- 
ting, such  applications  are  outside  the  realm  of  this  chapter.  The  surgeon, 
who  desires  additional  information  on  this  subject,  should  refer  to  other 
sources'-''^'  -*■  ~^  for  details  concerning  their  employment.  Short  wave  dia- 
thermy currents  are  not  suitable  for  fulguration,  desiccation  or  coagulation 
but  are  excellent  for  purposes  of  cutting.  A  conventional  diathermy, 
spark  gap,  apparatus  should  be  employed  for  fulguration,  desiccation 
or  coagulation. 

For  medical  purposes,  that  is  to  heat  the  bodily  tissues  within  physi- 
ological limits,  short  wave  diathermy  is  most  effective.  For  such  local 
heating  of  tissues  there  are  three  general  types  of  electrodes;  condenser 
plates  or  pads  may  be  placed  on  each  side  of  the  part  to  be  treated,  cuffs 
may  encircle  an  extremity  above  and  below  the  region  to  be  treated,  or  an 
induction  coil  may  be  wrapped  around  an  extremity  or  formed  in  the 
shape  of  a  flat  pancake  and  placed  over  a  certain  region.  The  electrodes 
always  should  be  spaced  away  from  the  bodily  surface  for  a  distance  of 
about  2  inches  (5  cm.)  by  means  of  felt  pads  or  folded  turkish  towels. 
The  apparatus  then  is  adjusted  to  provide  comfortable  warmth  in  the 
region  which  is  exposed  to  the  current. 

Despite  frequent  claims  that  short  exposures  of  not  more  than  ten 
minutes  are  sufficient  to  produce  proper  heating  of  the  tissues,  repeated 
studies  in  my  own  department-^  have  indicated  that  it  requires  at  least 
thirty  minutes  of  exposure  to  short  wave  diathermy  to  obtain  an  optimal 

Vol.  I.  941 


8io  (38)  PHYSICAL   MEDICINE 

increase  in  temperature,  and  the  usual  exposure  time  should  be  thirty  to 
forty-five  minutes.  For  further  details  concerning  the  technic  of  applica- 
tion of  short  wave  diathermy  other  more  complete  publications  should  be 
consulted'^'  -^. 

Short  wave  diathermy  has  been  recommended  especially  in  the  treat- 
ment of  suppurative  processes,  diseases  of  the  bones  and  joints  such  as 
sprains,  dislocations,  arthritis,  osteomyelitis  and  periostitis.  There  still  is 
considerable  argument  concerning  the  usefulness  of  short  wave  diathermy 
in  the  management  of  fractures.  Some  investigators  have  expressed  the 
belief  that  hyperemia  caused  by  diathermy  produces  demineralization  of 
bones,  whereas  others  have  felt  that  the  increased  circulation  accelerates 
the  formation  of  new  bone. 

Some  have  stated  that  the  heat  produced  by  diathermy  is  valuable  in 
the  treatment  of  fractures  because  of  its  favorable  influence  on  the  associ- 
ated injuries  to  soft  tissue.  When  so  employed,  it  often  should  be  ad- 
ministered in  conjunction  with  massage  and  exercise.  Diathermy  also 
has  been  recommended  in  the  treatment  of  various  types  of  endarteritis 
to  promote  circulation.  However,  in  such  cases  there  is  always  danger  of 
producing  burns  and  subsequent  gangrene,  if  too  intense  diathermy  is 
applied  directly  to  the  involved  extremity.  Its  employment  has  been 
recommended  also  in  treatment  for  varicose  ulcers. 

In  the  field  of  cutaneous  diseases  continental  workers  have  recom- 
mended particularly  that  diathermy  be  applied  for  furuncles,  carbuncles, 
cellulitis  and  paronychia.  To  date  there  is  no  conclusive  evidence  that 
diathermy  is  more  effective  in  such  localized  infections  than  are  other 
forms  of  mild  local  heating.  For  certain  gastrointestinal  diseases  such  as 
diverticulitis,  acute  enteritis  and  spastic  colitis  diathermy  has  seemed  to 
be  of  value  as  a  palliative  measure.  A  number  of  good  investigators  have 
stressed  the  value  of  local  applications  of  intrapelvic  diathermy  in  the 
treatment  of  chronic  inflammation  in  the  pelvic  region  as  well  as  for  non- 
specific prostatitis,  epididymitis  and  cystitis.  Among  the  diseases  of 
muscles,  tendons  and  bursae,  for  which  diathermy  has  been  recommended, 
may  be  mentioned  contusions,  muscular  strains,  myositis,  fibrositis,  teno- 
synovitis and  bursitis.  Among  the  diseases  of  the  nervous  system,  in 
which  local  heating  by  diathermy  sometimes  is  useful,  may  be  mentioned 
neuritis,  particularly  ischemic  neuritis  and  such  conditions  as  brachial 
neuritis,  intercostal  neuritis,  sciatica  and  trifacial  neuralgia.  Short  wave 
diathermy  has  been  recommended  to  promote  healing  and  to  allay  pain  in 
otitis  media  and  in  the  treatment  of  furunculosis  of  the  external  auditory 
canal. 

Among  diseases  of  the  respiratory  system,  for  which  short  wave  dia- 

VoL.  I.  941 


DIATHERMY  8io  (39) 

thermy  has  been  recommended,  may  be  mentioned  sinusitis.  Although 
after  adequate  drainage  has  been  estabUshed  local  applications  of  heat 
may  be  of  slight  value  in  the  presence  of  inflammation  of  the  accessory 
nasal  sinuses,  the  procedure  is  merely  palliative,  and  there  is  no  conclusive 
evidence  that  the  procedure,  as  often  has  been  claimed,  ever  is  a  specific 
in  this  condition.  Diathermy  has  been  recommended  also  as  an  adjunct 
in  the  management  of  various  pulmonary  lesions  such  as  bronchitis, 
bronchial  asthma  and  both  bronchial  and  lobar  pneumonia.  In  such 
conditions  it  must  be  considered  simply  as  another  means  of  applying 
heat,  and  it  should  be  employed  only  as  an  auxiliary  measure  in  conjunc- 
tion with  other  forms  of  treatment. 

Contraindications  to  the  Employment  of  Diathermy 

Diathermy  should  not  be  employed  in  the  treatment  of  any  condition 
in  which  there  is  danger  of  hemorrhage.  Because  of  the  danger  of  burns 
the  application  of  diathermy  is  contraindicated  also  over  regions  in  which 
sensation  is  impaired.  It  should  not  be  administered  to  the  abdomen, 
lower  portion  of  the  back  or  pelvis  during  pregnancy  or  during  the  men- 
strual period.  Also  it  should  not  be  applied  over  regions  in  which  there 
may  be  a  malignant  growth  or  tuberculous  lesion.  Some  authors  believe 
that  diathermy  should  not  be  applied  in  the  presence  of  phlebitis  because 
of  the  danger  of  embolism. 

Summary  of  Data  on  Diathermy 

It  is  wise  to  employ  only  such  diathermy  apparatus  as  has  been 
accepted  by  the  Council  on  Physical  Therapy  of  the  American  Medical 
Association.  The  various  diathermy  machines  which  have  been  con- 
sidered acceptable,  information  about  their  degree  of  efficiency  and  the 
approved  technics  for  their  use  are  listed  in  a  booklet  entitled  "Apparatus 
Accepted  by  the  Council  on  Physical  Therapy  of  the  American  Medical 
Association"'.  Every  effort  should  be  made  to  avoid  the  use  of  diathermy 
except  when  it  definitely  is  indicated.  Certainly  there  are  enough  rational 
indications  for  its  employment  to  warrant  its  frequent  use.  It  should  not 
be  forgotten,  however,  that  simpler  methods  of  applying  heat  may  be 
equally  effective  for  the  treatment  of  superficial  lesions.  Short  wave 
diathermy  finds  its  greatest  usefulness  for  treatment  of  deeper  lesions. 
It  unquestionably  is  the  most  valuable  form  of  electrotherapy  available 
today.  When  employed  in  a  rational  manner,  it  may  be  used  for  a 
multitude  of  purposes  both  in  medicine  and  in  surgery. 

Vol.  I.  941 


8io  (40)  PHYSICAL   MEDICINE 


BIBLIOGRAPHY  OF  ELECTROTHERAPY 

1.  COUNCIL  ON  PHYSICAL  THERAPY:    The  interrupted  low  frequency  and 

the  constant  electric  current  in  medicine,  in  Handbook  of  Physical  Therapy, 
Ed.  3,  pp.  205-213,  American  Medical  Association  Press,  Chicago,   1939. 

2.  MacKEE,   G.   M.:    The  treatment  of    skin    diseases    by    physical   therapeutic 

methods.  Jour.  Am.  Med.  Assoc,  1932,  XCVIII,  1646. 

3.  CIPOLLARO,    A.    C:     Electrolysis;     a   discussion   of   equipment,    method   of 

operation,  indications,  contraindications,  and  warning  concerning  its  use, 
in  Handbook  of  Physical  Therapy,  Ed.  3,  pp.  268-279,  American  Medical 
Association  Press,  Chicago,   1939. 

4.  FRIEL,   A.   R.:    Electric   Ionization;    a   Practical   Introduction   to  its  Use  in 

Medicine  and  Surgery,  Wood,  New  York,  1922. 

5.  LIERLE,  D.  M.  and  SAGE,  R.  A.:    Underlying  factors  in  the  zinc  ionization 

treatment  of  middle  ear  infections,  Ann.  Otol.,  Rhin.  and  Laryng.,  1932, 
XLI,  359- 

6.  HOLLENDER,    A.    R.:     Physical    Therapeutic    Methods    in    Otolaryngology, 

Mosby,  St.  Louis,  1937. 

7.  KOVACS,   J.:     Iontophoresis  of  varicose   ulcers.   Arch.    Phys.   Therapy,    1937, 

XVIII,  103. 

8.  KLING,  D.  H.:    Histamine  iontophoresis  in  rheumatic  and  peripheral  circula- 

tory disturbances,  Arch.  Phys.  Therapy,  1935,  XVI,  466. 

9.  KOTKIS,  A.  J.  and   MELCHIONNA,   R.   H.:    Physiologic   effects   of  acetyl- 

beta-methylcholine    chloride    by    iontophoresis;    preliminary   report,   Arch. 
Phys.  Therapy,  1935,  XVI,  528. 
ID.    KOVACS,  J.:    The  iontophoresis  of  acetyl-beta-methyl-choline  chloride  in  the 
treatment  of  chronic  arthritis  and  peripheral  vascular  disease.  Am.  Jour. 
Med.  Sci.,  1934,  CLXXXVHI,  32. 

11.  KOVACS,  R.  and  KOVACS,  J.:    Newer  aspects  of  iontophoresis  for  arthritis 

and  circulatory  disturbances.  Arch.  Phys.  Therapy,   1934,  XV,  593. 

12.  TOVEY,  D.  W. :    Copper  ionization  treatment  of  cervicitis,  (Spec.  Sect.),  Am. 

Med.,  1932,  XXXVIII,  2. 

13.  SMART,   M.:    The   Principles  of  Treatment  of  Muscles  and  Joints  by  Grad- 

uated Muscular  Contractions,  Oxford  University  Press,  London,   1933. 

14.  SMART,    M.:     Graduated    Muscular    Contractions;     a    Short    Description    of 

Principles  and  Technique,  Oxford  University  Press,  London,   1936. 

15.  CUMBERBATCH,   E.   P.:    Essentials  of  Medical   Electricity,   Ed.   6,   Mosby, 

St.  Louis,   1929. 

16.  KRUSEN,  F.  H.:    Physical  Medicine,  Saunders,  Philadelphia,  1941. 

17.  KOVACS,   R. :    Electrotherapy  and  Light  Therapy,   Ed.   3,   Lea  and   Febiger, 

Philadelphia,  1938. 

18.  CUMBERBATCH,    E.    P.:     Essentials    of    Medical    Electricity,    Ed.    8,    The 

Sherwood  Press,  Cleveland,   1939. 

19.  CHOR,   H.,   CLEVELAND,   D.,   DAVENPORT,   H.  A.,   DOLKART,   R.   E. 
Vol.  I.  941 


BIBLIOGRAPHY  8io  (41) 

and  BEARD,  G. :  Atrophy  and  regeneration  of  the  gastrocnemius-soleus 
muscles;  effects  of  physical  therapy  in  the  monkey  following  section  and 
suture  of  sciatic  nerve,  Physiotherapy  Rev.,  1939,  XIX,  340. 

20.  OBER,  F.  R.:    Physical  therapy  in  infantile  paralysis,  Jour.  Am.  Med.  Assoc, 

1938,  CX,  45. 

21.  FISCHER,    E. :    The  effect  of  a   faradic  and   galvanic  stimulation   upon   the 

course   of   atrophy   in    denervated    skeletal    muscles.   Am.    Jour.    Physiol., 

1939,  CXXVII,  605. 

22.  HEMINGWAY,  A.  and  STENSTROM,   K.   W.:    Physical   characteristics  of 

short  wave  diathermy,  in  Handbook  of  Physical  Therapy,  Ed.  3,  American 
Medical  Association  Press,  Chicago,   1939. 

23.  MOCK,  H.  E. :  Electrosurgery  in  thyroidectomy.  Jour.  Am.  Med.  Assoc,  1930, 

XCIV,   1365. 

24.  KRUSEN,  F.  H.  and  ELKINS,  E.  C:   Electrosurgery,  South.  Surgeon,   1938, 

VII,  61. 

25.  KRUSEN,   F.   H.   and  SCHULHOF,   M.   G.:     Electrosurgery,  in   The  Cyclo- 

pedia of  Medicine,  Surgery  and  Specialties,  pp.  454-469,  Davis,  Phila- 
delphia, 1939. 

26.  KRUSEN,  F.  H.:   Short-wave  diathermy.  Military  Surgeon,  1940,  LXXXVII, 

158. 

27.  BIERMAN,  WILLIAM:    The  Medical  Applications  of  the  Short  Wave  Cur- 

rent, Wood,  Baltimore,  1938. 

Sept.  I,  1941. 


Vol.  I.  941 


8io  (42)  PHYSICAL   MEDICINE 


MASSAGE 

"Massage"  is  a  term  used  to  describe  a  group  of  systematic  and  scien- 
tific manipulations  of  the  tissues  of  the  body  which  are  performed  best 
with  the  hands  for  the  purpose  of  affecting  the  general  circulation  and  the 
nervous  and  muscular  systems. 

A  better  understanding  by  physicians  of  the  subject  of  massage  un- 
doubtedly would  lead  to  its  more  extensive  use  and  to  methods  of  appli- 
cation which  would  be  more  suitable  for  the  individual  patient.  Too 
frequently  the  physician  requests  a  technician  to  give  a  patient  "some  mas- 
sage" without  specifying  the  type,  duration  or  other  details  concerning 
the  method  of  massage  to  be  followed.  Although  on  the  European  con- 
tinent it  frequently  is  the  custom  for  the  physician  himself  to  apply 
massage,  among  American  and  British  physicians  it  usually  is  customary 
to  delegate  this  work  to  technicians.  Because  of  the  fact  that  in  the 
United  States  there  are  skillful  registered  physical  therapy  technicians 
and  in  Britain  well  trained  members  of  the  Chartered  Society  of  Massage 
and  Medical  Gymnastics,  who  are  well  instructed  in  anatomy  and  kines- 
iology, the  custom  usually  is  acceptable.  Nevertheless  even  the  most 
skillful  technician  is  untrained  in  diagnosis  and  has  only  a  limited  knowl- 
edge of  morbid  physiology  and  pathology,  so  that  the  physician  always 
should  assume  direct  supervision  of  the  massage,  even  though  the  techni- 
cian does  the  actual  work. 

MennelP  said  pertinently:  "When  a  medical  man  orders  massage  he 
should  not  try  to  hand  over  his  responsibility  to  the  masseur.  He  should 
consider  the  prescription  of  massage  treatment  in  the  same  light  as  he 
would  consider  that  of  a  potent  drug  and  watch  its  effects  no  less  closely, 
varying  the  dose  and  the  nature  of  the  dose  from  time  to  time  according 
to  indications." 

Methods  of  Applying  Massage 

The  massage  movements  in  the  order  of  their  importance  are  as 
follows;  (i)  efifleurage  (stroking),  (2)  petrissage  (kneading),  (3)  friction 
(a  circular  rolling  movement),  (4)  tapotement  (percussion)  and  (5)  vibra- 
tion (a  tremulous  or  vibratory  movement). 

Stroking,  kneading  and  friction  are  the  only  movements  which  are 
employed  routinely  for  therapeutic  purposes.  Vibratory  and  percussion 
movements  usually  are  applied  to  the  healthy  individual  and  rarely  are 
applied  to  the  sick  person. 

Vol.  I.  941 


METHODS   OF   APPLYING   MASSAGE  8io  (43) 

Effleurage  or  Stroking.  —  Stroking  is  the  most  common  form  of  mas- 
sage. The  hand  is  moved  slowly,  gently  and  rhythmically  in  long,  strok- 
ing movements.  Light,  superficial  stroking  produces  reflex  effects,  and 
deep  stroking  will  produce  actual  mechanical  emptying  of  the  veins  and 
lymphatic  vessels. 

Petrissage  or  Kneading.  —  Kneading  is  a  wringing  or  compression 
movement  in  which  the  muscles  are  picked  up  and  rolled,  squeezed  or 
wrung. 

Friction.  —  Friction  is  not,  as  the  name  might  suggest,  a  rapid  rubbing 
of  the  technician's  hand  over  the  skin  to  produce  a  frictional  effect.  On 
the  contrary,  it  is  a  circular,  rolling  movement,  in  which  the  patient's 
skin  is  moved  over  the  subcutaneous  structures  in  small  circles.  The 
fingers  of  the  masseur  remain  at  one  point  on  the  patient's  skin  and  move 
it  around.  This  type  of  massage  tends  to  loosen  superficial  scars  and 
adhesions.     Friction  usually  is  preceded  and  followed  by  stroking. 

Tapotenient  or  Percussion.  —  There  are  various  types  of  percussion. 
If  the  surface  of  the  patient's  body  is  struck  lightly  and  alternately  first 
with  the  ulnar  surface  of  one  hand  and  then  with  the  ulnar  surface  of  the 
other  hand,  the  procedure  is  called  "hacking".  If  the  part  is  struck 
lightly  and  rapidly  with  alternate  slightly  cupped  palms  of  the  hands,  the 
procedure  is  called  "cupping".  If  the  tips  of  the  fingers  are  employed 
for  percussion,  the  method  is  spoken  of  as  "tapping".  When  the  flattened 
palms  are  employed  for  percussion,  the  procedure  is  termed  "slapping". 
Finally,  if  the  relaxed  half-clenched  fists  are  used  for  percussion,  the 
designation  "beating"  is  employed.  Percussion  movements  will  produce 
stimulating  effects  and  induce  peripheral  hyperemia. 

Vibration.  —  Vibration  is  a  continuous  trembling  movement  which  is 
applied  to  the  surface  of  the  patient's  body  through  the  tips  of  the 
technician's  fingers  or  through  his  whole  hand.  The  vibratory  movement 
is  initiated  by  the  muscles  of  the  technician's  shoulder  and  forearm.  It 
is  an  extremely  difficult  movement  and  soon  tires  the  masseur.  For  this 
reason  in  the  few  instances,  in  which  vibration  is  required,  a  mechanical 
device  may  be  attached  to  the  back  of  the  technician's  hand  to  produce 
the  vibratory  movement. 

In  most  instances  the  numerous  mechanical  devices,  which  have  been 
marketed  in  profusion  for  pushing,  pulling,  twisting,  turning  and  other- 
wise manipulating  the  human  contours,  are  utterly  useless.  For  example 
about  ten  years  ago  the  public  was  swept  with  a  wave  of  enthusiasm  for 
machines  which  allegedly  supplied  massage  and  exercise  by  means  of  a 
strong  vibrator  attached  to  a  wide  belt.  These  so-called  health  exercisers 
were  much  in  vogue  for  a  short  time,  but  because  they  were,  like  most 

Vol.  I.  941 


8io  (44)  PHYSICAL   MEDICINE 

such  devices,   almost  useless  as  a  means  of  applying  either  massage  or 
exercise,  they  soon  fell  into  disrepute. 

In  1930  Pemberton,  Coulter  and  Mock-  commented  concerning  these 
"health  exercisers"  as  follows:  "Doctor  Gustaf  Zander  of  Stockholm, 
about  1857,  was  the  first  to  use  mechanical  means  for  massage  and  ex- 
ercise. His  machines  will  do  anything  that  any  of  the  highly  advertised 
mechanical  vibrators  will  do.  These  machines  were  given  a  trial  in  this 
country,  and  several  large  hospitals  completely  equipped  Zander  rooms. 
These  forms  of  apparatus  have  fallen  into  disuse,  as  will  the  present 
widely  advertised  mechanical  exercisers."  The  prediction  of  these  physi- 
cians was  correct;  the  "health  exerciser"  no  longer  is  heard  of,  and  such 
has  been  the  case  with  all  similar  mechanical  massaging  devices. 

Physical  Principles  Concerned  in  the  Application 
OF  Massage 

Massage  is  an  entirely  mechanical  procedure.  Usually  the  hands  of  a 
skilled  masseur  or  masseuse  serve  as  the  therapeutic  agents.  Mechanical 
apparatus  of  various  types  has  not  proved  suitable  for  massage  because 
the  movements  are  too  complex  to  be  produced  satisfactorily  by  a  ma- 
chine. 

MennelP  said  that  only  two  possible  effects  were  obtainable  from  mas- 
sage, a  mechanical  effect  and  a  reflex  effect.  It  generally  is  believed  that 
superficial  stroking  will  produce  reflex  diminution  of  muscular  spasm. 
Physicians  usually  are  more  familiar  with  reflexes,  such  as  the  cremasteric 
or  the  plantar  reflexes,  which  are  produced  by  irritation  of  the  skin  and 
cause  muscular  contraction,  and  often  they  have  not  realized  that  the 
soothing  effect  of  light  stroking  of  the  skin  may  produce  reflex  muscular 
relaxation.  It  is  easy  to  demonstrate  such  reflex  muscular  relaxation  by 
applying  superficial  rhythmic  stroking  in  the  presence  of  a  recent  fracture 
with  associated  muscular  spasm.  The  gentle  stroking  often  produces 
sufficient  relaxation  to  permit  easier  reduction  of  the  fracture. 

Action  and  Uses  of  Massage 

Pemberton^  said  aptly:  "There  is  probably  no  other  measure  of  equal 
known  value  in  the  entire  armamentarium  of  medicine  which  is  so  inade- 
quately understood  and  utilized  by  the  profession  as  a  whole."  Mennell^, 
Coulter^  and  Pemberton^  all  have  made  definite  contributions  to  our 
modern  knowledge  of  the  action  of  massage.  Massage  can  be  employed 
for  its  direct  action  on  the  surface  of  the  skin  to  remove  detritus  and  ex- 

VoL.  I.  941 


ACTION   AND   USES   OF   MASSAGE  8io  (45) 

cessive  secretions  and  to  cleanse  the  openings  of  sweat  and  sebaceous 
glands.  This  procedure  is  particularly  useful  at  the  time  of  removal  of 
splints  or  casts  following  fracture.  Rosenthal^  found  that  massage  of  the 
skin  could  cause  an  increase  of  local  temperature  of  3.6°  to  5.4°  F.  (2° 
to  3°  C).  He  attributed  these  increases  of  temperature  not  only  to  direct 
mechanical  action  but  also  to  indirect  vasomotor  effects. 

The  mistaken  general  impression  still  exists  that  massage  will  remove 
deposits  of  fat  from  local  regions  of  the  body.  Careful  clinical  investiga- 
tions do  not  support  this  impression.  In  experimental  studies  of  this 
problem  Rosenthal^  found  that  vigorous  massage  of  the  abdominal  wall 
of  animals  produced  no  destructive  effect  on  the  adipose  tissue.  Following 
the  heavy  massage  histological  sections  of  the  adipose  tissue  exhibited  no 
destruction  of  the  fat,  although  the  pressure  of  the  massage  had  been 
sufficiently  heavy  to  produce  multiple  hemorrhages. 

It  is  believed^  that  massage  of  muscles  may  improve  the  supply  of 
blood  and  tend  to  remove  the  excess  of  lactic  acid  which  develops  follow- 
ing exercise.  Massage  can  be  employed  as  a  mechanical  means  of  stretch- 
ing or  breaking  adhesions  of  intramuscular  connective  tissue.  Although 
it  often  is  thought  that  massage  of  muscles  may  increase  their  strength, 
this  is  not  the  case.  Muscular  strength  can  be  improved  only  by  active 
exercise. 

Centripetal  stroking  will  improve  circulation  by  aiding  mechanically 
the  return  of  venous  blood  and  lymph  toward  the  heart.  It  may  produce 
also  reflex  contraction  of  the  unstriped  muscles  of  the  walls  of  the  vessels, 
thus  assisting  in  the  maintenance  or  restoration  of  the  tone  of  these 
muscular  fibers.  The  lightest  stroking  will  empty  the  superficial  veins 
and  lymphatic  vessels  of  an  extremity,  and  the  pressure  in  the  deeper 
veins  rarely  exceeds  that  of  5  or  10  mm.  of  mercury.  In  order  to  obtain 
mechanical  assistance  to  circulation  in  the  deeper  vessels,  the  muscles 
must  be  well  relaxed. 

Best  and  Taylor^  pointed  out  that  light  stroking  causes  the  "white 
reaction",  which  attains  its  maximal  intensity  in  thirty  to  sixty  seconds 
and  then  gradually  fades  in  about  three  to  five  minutes.  They  concluded 
that  this  reaction  did  not  have  a  nervous  basis  but  was  due  to  direct 
stimulation  of  the  walls  of  the  capillaries.  They  thought  that  heavy 
stroking  would  produce  more  enduring  dilatation. 

Massage  often  is  valuable  as  an  adjunct  to  elevation  in  the  relief 
of  edema  of  an  extremity.  Massage  will  assist  gravity  and  also  aid  in 
restoring  vasomotor  tone. 

Observations^  through  a  permanent  window  of  the  capillary  circula- 
tion of  the  ear  of  a  rabbit  have  revealed  that  following  massage  there  is  an 

Vol.  I.  941 


8io  (46)  PHYSICAL   MEDICINE 

increase  in  the  rate  of  flow  of  blood  and  a  change  in  the  walls  of  the 
capillaries  which  is  evidenced  by  sticking  and  emigration  of  leukocytes.  It 
was  concluded  that  the  massage  produced  an  increased  interchange  of 
substances  between  the  blood  stream  and  tissue  cells  with  an  altered  and 
presumably  improved  metabolism  of  tissues. 

For  necessarily  inactive  patients  and  especially  for  patients  with 
cardiac  decompensation  massage  can  be  employed  to  compensate  for  the 
lack  of  contraction  of  the  muscles  of  locomotion  which  normally  contrib- 
utes to  the  return  of  venous  blood  to  the  heart.  I  agree  with  Pemberton^ 
that  this  form  of  massage  "is  not  utilized  clinically  to  the  extent  that  it 
should  be". 

It  is  said  that  the  influence  of  massage  in  increasing  the  amount  of 
hemoglobin  and  the  number  of  erythrocytes  of  the  circulating  blood  "is 
beyond  question".  Massage  does  not  increase  the  lactic  acid  content  of 
the  blood,  and  the  change  in  the  hydrogen  ion  concentration  is  not  com- 
parable to  that  observed  following  exercise.  Massage  produces  no  change 
in  the  percentage  of  oxygen  saturation,  but  it  does  cause  a  slight  rise  in 
the  oxygen  capacity  of  the  blood. 

If  massage  is  applied  skillfully,  it  can  be  employed  to  produce  either 
a  sedative  or  a  stimulating  effect  on  the  central  nervous  system.  Massage 
does  not  have  any  immediate  eff^ect  or  great  influence  on  general  metabo- 
lism. There  is  no  immediate  or  delayed  effect  on  the  basal  consumption 
of  oxygen,  the  pulse  rate  or  blood  pressure  of  normal  persons. 

Arthritis.  —  Massage  is  of  considerable  value  in  preventing  or  delaying 
the  muscular  atrophy  which  often  is  associated  with  arthritis.  Properly 
applied,  it  can  be  employed  also  in  arthritis  to  improve  local  metabolism, 
increase  circulation  and  lessen  edema.  In  most  cases  of  arthritis  massage 
is  preceded  by  applications  of  heat  and  followed  by  exercise.  For  atrophic 
arthritis  massage  alone  is  useless.  Usually  massage  is  applied  to  the 
muscles  above  and  below  the  joint  rather  than  directly  to  the  arthritic 
joint.  In  the  management  of  atrophic  arthritis  general  massage  often 
can  be  employed  advantageously  in  conjunction  with  local  massage. 
In  hypertrophic  arthritis  especial  care  must  be  exercised  to  avoid  heavy 
massage  over,  or  too  close  to,  the  articular  structures.  Massage  never 
should  add  to  the  trauma  which  already  has  been  inflicted  on  such  joints. 

A  leading  specialist^  on  arthritis  said  that  "few,  if  any,  advanced 
cases  of  arthritis  of  either  the  atrophic  or  the  hypertrophic  type  .  .  .  can 
be  expected  to  recover  without  recourse  to  the  principles  of  physical 
therapy,  intelligently  ordered  rest  and  massage  in  particular". 

Fihrositis.  —  Many  English  writers  have  urged  the  employment  of  a 
special  type  of  extremely  firm  massage  in  treatment  for  fibrositis  of  either 

Vol.  I.  941 


ACTION   AND    USES   OF    MASSAGE  8io  (47) 

the  intramuscular  or  the  periarticular  type.  All  these  authors"-  ^"-  "•  '-•  ^^ 
agreed  that  in  conjunction  with  fibrositis,  fibrous  nodules  will  be  found 
which  can  be  "massaged  away". 

Despite  the  fact  that  this  condition  commonly  is  unrecognized  in  the 
United  States,  it  seems  safe  to  conclude  that  the  numerous  English  ob- 
servers are  correct  in  their  conclusions.  They  contended  that  there  is  a 
form  of  muscular  rheumatism,  commonly  called  "fibrositis",  which  is 
characterized  by  the  formation  of  fibrous  nodules,  bands  or  indurated 
regions,  which  are  acutely  tender  at  first  and  are  associated  with  muscular 
spasm,  and  that,  if  the  condition  becomes  chronic,  the  tenderness  and 
muscular  spasm  tend  to  disappear. 

Furthermore  English  physicians  have  claimed  repeatedly  that  such  in- 
durations can  be  broken  up  and  made  to  disappear  by  means  of  a  special 
type  of  heavy  stroking  and  kneading  which  should  be  applied  directly  to 
the  indurations.  The  heavy  massage,  if  continued  for  a  sufficiently  long 
period,  tends  to  relieve  pain,  tenderness  and  muscular  spasm.  Apparently 
fibrositis  frequently  is  overlooked,  and  the  value  of  heavy  massage  in 
treatment  often  has  been  unrecognized.  The  procedure  is  palliative  rather 
than  curative,  and  recurrences  are  frequent,  so  that  often  it  will  be  neces- 
sary to  employ  other  methods  of  treatment  in  conjunction  with  renewed 
applications  of  firm  massage. 

Diseases  of  the  Muscles.  —  In  muscular  spasm  of  the  occupational  type, 
such  as  "writer's  cramp",  a  small  localized  region  of  tenderness  often  is 
present.  Friction  and  deep  stroking  frequently  relieve  such  tenderness. 
Continued  deep  stroking  and  kneading  may  prove  to  be  a  valuable  adjunct 
in  treatment. 

Brisk  general  massage  in  conjunction  with  stroking  and  kneading  of 
the  affected  regions  has  been  employed  in  treatment  for  pseudohyper- 
trophic muscular  dystrophy.  The  massage  usually  is  administered  in 
conjunction  with  the  passive  exercise  of  joints  to  prevent  contractures. 
These  procedures,  of  course,  are  merely  palliative. 

For  muscular  contusions  gentle  stroking  and  later  kneading  may  be 
valuable  in  relieving  pain  and  stiffness  and  in  promoting  absorption  of 
exudate.  The  massage  should  not  be  begun  until  forty-eight  hours  after 
the  injury  was  sustained. 

Obesity.  —  It  has  been  mentioned  that  massage  is  incapable  of  re- 
moving local  deposits  of  adipose  tissue,  but  general  massage  employed 
in  conjunction  with  exercise  and  reduction  of  caloric  intake  may  be  of 
slight  usefulness  in  the  management  of  obesity.  The  massage  sometimes 
can  be  employed  as  an  adjunct  in  the  early  treatment  of  weak,  obese 
individuals;    later  it  can  be  replaced  by  carefully  graduated  mild  exercises. 

Vol.  I.  941 


8io  (48)  PHYSICAL   MEDICINE 

Circulatory  Diseases.  —  When  there  is  cardiac  decompensation,  skillful 
massage  may  aid  in  restoring  compensation  by  improving  the  peripheral 
circulation.  Curiously  enough,  although  massage  has  an  obvious  field  of 
usefulness  in  improving  circulation,  and  although  it  frequently  is  employed 
for  this  purpose  on  the  European  continent,  it  rarely  is  put  to  this  use 
by  American  physicians.  Every  clinician  determines  the  presence  of 
edema  by  making  pressure  with  a  finger  to  displace  fluids.  It  is  obvious 
that  massage  could  perform  the  same  function  on  a  larger  scale  and  free 
an  extremity  of  some  of  the  edema.  This  fact,  however,  seems  "to  have 
escaped  large  recognition  in  this  country*". 

Furthermore  in  cases  of  circulatory  failure,  when  the  patient  must  re- 
main at  absolute  rest,  massage  can  be  employed  as  a  substitute  for  the 
normal  muscular  contractions  which  usually  assist  circulation.  Moderately 
deep  stroking  sometimes  can  be  employed  in  conjunction  with  other  thera- 
peutic measures  in  treatment  of  peripheral  vascular  diseases. 

Neurological  Diseases.  —  Massage  sometimes  is  employed  to  combat 
the  fatigue,  depression  and  irritability  often  associated  with  neurasthenia. 
Massage  sometimes  can  be  employed  to  advantage  in  the  management  of 
hysteria,  but  the  technician  must  be  familiar  with  psychotherapeutic 
methods  and  must  employ  massage  only  as  it  may  be  needed.  For  most 
neuroses  massage  should  not  be  used  indiscriminately.  Coulter^  has  said 
that  in  most  cases  of  traumatic  neurosis  "more  symptoms  have  been 
rubbed  in  with  massage  than  have  been  rubbed  out". 

Massage  has  been  employed  as  a  palliative  measure  in  the  management 
of  such  neurological  conditions  as  Parkinson's  syndrome,  syringomyelia 
and  Sydenham's  chorea.  Light  sedative  massage  occasionally  is  used  in 
treatment  of  peripheral  neuritis.  In  certain  forms  of  paralysis,  such  as 
"crutch  paralysis"  and  "Bell's  palsy",  massage  can  be  very  useful  in 
maintaining  tone  and  nutrition  of  the  muscles  until  volitional  control 
returns. 

Orthopedic  Conditions.  —  Massage  has  been  employed  for  sprains, 
strains,  dislocations  and  fractures  to  promote  circulation,  relieve  muscular 
spasm,  overcome  adhesions  and  restore  function.  It  is  valuable  also  in 
conjunction  with  exercise  in  the  management  of  postural  backache,  sacro- 
iliac or  lumbosacral  strain  and  coccygodynia.  In  the  latter  condition 
both  external  and  internal  massage  are  employed  occasionally.  In  some 
instances  coccygodynia  seems  to  be  due  to  spasm  of  the  piriformis, 
coccygeus  and  levator  ani  muscles,  and  such  spasm  sometimes  can  be 
relieved  by  internal  massage  through  the  rectum. 

Following  amputation  massage  often  is  useful  in  the  preparation  of 
the  stump  to  receive  the  prosthesis. 

Vol.  I.  941 


BIBLIOGRAPHY  8io  (49) 

Obstetrical  Conditions.  —  Massage  frequently  is  valuable  during  and 
following  the  puerperium.  Certain  conditions  which  contribute  to  the 
discomforts  of  pregnancy  can  be  benefited  distinctly  by  correct  applica- 
tion of  massage.  These  include  nervous  headaches,  cramps  of  the  legs, 
backache  resulting  from  muscular  strain  and  mild  edema  of  the  legs 
resulting  from  simple  venous  obstruction.  During  labor  massage  of  the 
uterus  often  is  employed  by  the  obstetrician.  Following  delivery  massage 
of  the  fundus  of  the  uterus  is  practiced  in  order  to  hasten  involution. 
On  the  third  day  after  delivery  massage  of  the  legs  can  be  started. 

Contraindications  to  the  Application  of  Massage 

Massage  should  not  be  employed  in  the  presence  of  malignant  growths, 
acute  inflammatory  processes,  certain  cutaneous  affections  such  as  eczema 
and  acne,  tuberculous  lesions,  acute  systemic  diseases  which  are  accom- 
panied by  fever,  acute  phlebitis,  thrombosis  or  lymphangitis.  Other 
conditions,  which  contraindicate  the  employment  of  massage,  are  un- 
drained  osteomyelitis,  gastric  or  duodenal  ulcer,  hernia,  debilitating  dis- 
eases, advanced  arteriosclerosis,  abscesses,  aneurysm,  advanced  nephritis 
and  acute  communicable  diseases.  Heavy  massage  should  not  be  applied 
to  the  abdomen  during  the  later  months  of  pregnancy. 

Summary  of  Data  on  Massage 

There  is  a  distinct  need  for  a  better  understanding  on  the  part  of 
physicians  of  the  action  and  uses  of  massage.  Its  limitations  also  should 
be  known.  Massage  can  be  employed  satisfactorily  only  if  each  step  in 
its  application  is  directed  properly  by  a  physician,  who  is  familiar  with 
its  effects,  and  who  knows  how  to  modify  them  to  suit  the  indications. 
The  numerous  contraindications  to  the  use  of  massage  always  should  be 
kept  in  mind. 

BIBLIOGRAPHY   OF   MASSAGE 

1.  MENNELL,  J.  B.:    Massage;    its  Principles  and  Practice,  Ed.  2,  Blakiston, 

Philadelphia,  1920. 

2.  PEMBERTON,   R.,   COULTER,  J.  S.  and   MOCK,   H.  E.:    Massage,  Jour. 

Am.  Med.  Assoc,  1930,  XCIV,  1989. 

3.  PEMBERTON,  R. :    Physiology  of  massage,  in  Handbook  of  Physical  Therapy, 

pp.  78-87,   Ed.  3,  American  Medical  Association  Press,   Chicago,   1939. 

4.  MENNELL,    J.    B.:     Physical    Treatment    by    Movement,    Manipulation   and 

Massage,  Blakiston,  Philadelphia,  1934. 
Vol.  I.  941 


8io  (50)  PHYSICAL   MEDICINE 

5.  COULTER,  J.  S.:  Massage,  in  PIERSOL,  G.  M.:   The  Cyclopedia  of  Medicine, 

Vol.  VIII,  pp.  598-617,  Davis,  Philadelphia,  1933. 

6.  ROSENTHAL,  C:    Quoted  by  Pemberton,  R.^. 

7.  BEST,  C  H.  and  TAYLOR,  N.  B.:   The  Physiological  Basis  of  Medical  Prac- 

tice;  a  University  of  Toronto  Text  in  Applied  Physiology,  Ed.  2,  Williams 
and  W'ilkins,  Baltimore,  1939. 

8.  PEMBERTON,   R. :    Massage  in  internal  medicine,  in  Handbook  of   Physical 

Therapy,  Ed.  3,  pp.  105-114,  American  Medical  Association  Press,  Chicago, 

1939- 

9.  STOCKMAN,    R. :     Rheumatism   and   Arthritis,    Green   and   Son,    Edinburgh, 

1920. 

10.  COPEMAN,  VV.   S.   C:    The  Treatment  of  Rheumatism  in  General   Practice, 

Wood,  Baltimore,   1933. 

11.  POYNTON,  F.  J.  and  SCHLESINGER,  B.:   Recent  Advances  in  the  Study  of 

Rheumatism,  Blakiston,  Philadelphia,  193 1. 

12.  THOMSON,  F.  G.  and  GORDON,  R.  G.:   Chronic  Rheumatic  Diseases;   their 

Diagnosis  and  Treatment,  Oxford  University  Press,  Edinburgh,  1926. 

13.  CYRIAX,  E.:    On  fibrositis  of   the  neck,  Brit.  Jour.  Phys.  Med.,  1935,  X,  49. 

Sept.  I,  1941. 


Vol.  I.  941 


THERAPEUTIC   EXERCISE  8io  (51) 

CORRECTIVE  OR  THERAPEUTIC   EXERCISE 

The  methods  of  exercise  employed  in  modern  therapy  have  sprung 
from  three  systems  of  exercise;  (i)  the  Swedish  system  introduced  by 
Ling  and  Spiess,  (2)  the  Turnverein  system  founded  in  Germany  by 
Jahn  and  (3)   the  Delsarte  system  developed  by  the  French. 

The  modern  American  technician,  as  a  rule,  does  not  follow  any  one  of 
these  systems  but  has  adopted  that  which  is  best  from  all  of  them  and 
has  introduced  much  in  addition.  The  Swedish  system  for  some  reason 
has  caught  the  popular  fancy  in  this  country,  and  many  physicians  as 
well  as  laymen  have  the  erroneous  fancy  that  anyone  who  is  a  native  of 
Sweden  is  endowed  with  great  skill  in  massage  and  gymnastics.  As  a 
matter  of  fact  the  American  physician,  who  is  familiar  with  modern  cor- 
rective exercise,  immediately  becomes  suspicious  of  the  individual  who 
claims  to  be  an  expert  in  Swedish  exercises,  because  he  knows  that  the 
modern  American  technician  should  be  familiar  with  the  best  methods 
of  exercise  derived  from  all  the  ancient  systems  and  should  not  confine 
himself  to  one  system  only. 

Today  the  old  systems  and  the  Zander  equipment  no  longer  are  em- 
ployed in  the  hospitals.  Corrective  or  therapeutic  exercises  now  are 
administered,  usually  as  free  exercises  without  the  aid  of  apparatus,  by 
skilled  technicians  who  are  well  trained  in  anatomy  and  kinesiology. 
Working  under  direct  medical  supervision,  such  technicians  are  capable  of 
providing  an  infinite  variety  of  corrective  exercises  which  can  be  modified 
from  day  to  day  to  fit  the  needs  of  the  individual  patient. 

The  scope  of  therapeutic  exercise  is  much  broader  than  most  physicians 
realize.  It  is  apparent  that  every  physician  should  be  familiar  with  the 
various  forms  of  corrective  exercise,  and  that  the  supervision  of  the 
therapeutic  exercises  should  be  entirely  in  his  hands.  As  is  the  case  with 
regard  to  massage,  or  for  that  matter,  any  form  of  treatment,  the  respon- 
sibility should  not  be  delegated  to  a  layman. 

Corrective  or  therapeutic  exercise  can  be  defined  as  "the  scientific 
application  of  bodily  movement  designed  specifically  to  maintain  or  to 
restore  normal  function  to  diseased  or  injured  tissues".  Exercise  can  be 
employed  to  rehabilitate  patients  suffering  from  a  wide  variety  of  dis- 
eases. 

Methods  of  Applying  Therapeutic  Exercise 

Exercises  can  be  performed  either  actively  or  passively.      In   passive 
exercise  the  motion  of  a  segment  of  the  body  is  imparted  by  some  out- 
VoL.  I.  941 


8io  (52)  PHYSICAL   MEDICINE 

side  force.  The  outside  force  usually  is  derived  from  the  hands  of  the 
technician  but  can  be  obtained  also  from  voluntary  effort  of  another 
segment  of  the  patient's  own  body  or  from  a  machine.  Active  exercise  is 
accomplished  by  volitional  movement  by  the  patient  of  the  involved 
segment  or  segments  of  the  body. 

Therapeutic  exercise  is  classified  best  under  four  headings;  (i)  passive 
exercise  or  relaxed  movement,  (2)  active  assistive  exercise,  in  which  the 
patient  makes  a  voluntary  movement  and  is  assisted  in  making  it  by  the 
technician  or  by  some  other  force,  (3)  active  or  free  exercise  and  (4)  ac- 
tive resistive  exercise,  in  which  the  patient  makes  a  voluntary  effort 
to  move  the  part  and  is  resisted  in  such  movement  by  the  technician, 
by  some  other  outside  force  or  by  his  own  physiologically  antagonistic 
muscles. 

Passive  exercise  may  vary  from  the  gentlest  of  slow  rhythmic  move- 
ments, such  as  are  employed  in  the  early  stages  of  post-fracture  mobiliza- 
tion, to  the  extremely  forceful  movements,  sometimes  used  to, overcome 
fibrous  ankylosis  of  joints,  which  are  so  rigorous  that  they  must  be 
administered  only  when  the  patient  is  anesthetized.  Practically  all  forms 
of  manipulative  surgical  procedures  can  be  classified  under  the  heading  of 
passive  exercise.  Between  the  two  extremes  of  passive  exercise  lie  various 
gradations  of  passive  movement  which  must  be  understood  thoroughly  by 
the  technician. 

Although  active  exercises  usually  result  in  movement  of  joints,  there 
is  one  form  which  frequently  is  employed  for  therapeutic  purposes,  in 
which  movement  of  the  joints  does  not  occur.  This  form  of  active  ex- 
ercise is  called  static  exercise  or  muscle  setting.  In  muscle  setting  the 
patient  simply  contracts  and  relaxes  a  muscle  or  a  group  of  muscles 
without  moving  a  joint.  The  procedure  has  been  likened  to  a  "muscle 
dance"  and  has  the  advantage  of  maintaining  circulation  and  muscular 
tone  and  of  preventing  atrophy  without  disturbing  the  position  of  bones 
and  joints.  It  often  is  employed  to  exercise  the  muscles  of  an  extremity 
during  a  period  of  enforced  immobilization. 

Correct  use  of  resistive  exercise  often  is  the  only  way  to  make  one  group 
of  muscles  work  alone  and  to  exclude  its  antagonists. 

Physical  Principles  Concerned  in  the  Application 
OF  Therapeutic  Exercise 

As  with  any  mechanical  device  in  the  mechanical  acts  of  the  human 
body  movement  is  obtained  by  the  action  of  a  force  on  a  lever.  Each  of 
the  434  skeletal  muscles  is  a  simple  independent  force  capable  of  pro- 

VoL.  I.  941 


ACTION  AND   USES  8io  (53) 

ducing  motion.  These  muscles  act  on  the  three  orders  of  levers  commonly 
encountered  in  the  skeletal  mechanism. 

With  a  lever  of  the  first  order  the  joint,  which  serves  as  the  fulcrum, 
lies  between  the  weight  and  the  insertion  of  the  muscle  which  serves  as 
the  power.  With  a  lever  of  the  second  order  the  weight  lies  between  the 
point  of  application  of  power  and  the  joint.  With  a  lever  of  the  third 
order,  the  type  most  commonly  found  in  the  human  body,  the  power  is 
applied  at  a  point  between  the  weight  and  the  fulcrum. 

The  great  importance  of  the  normal  functioning  of  these  mechanisms 
in  preserving  health  is  stressed  by  MackenzieS  who  thought  that  in 
most  instances  health  depended  on  "a  correlation  of  all  the  bodily  systems 
to  the  erect  posture",  and  ill  health  depended  on  "a  failure  of  one  or  more 
systems  to  correlate  to  it". 

No  matter  which  order  of  lever  is  encountered  in  the  human  body, 
practically  all  of  them  are  arranged  so  that  the  distance  between  the 
fulcrum  and  the  point  of  application  of  power  is  short.  For  this  reason 
even  a  slight  pathological,  muscular  contracture  may  cause  a  relatively 
marked  angulation  of  a  joint.  Also  with  this  type  of  lever  a  muscle  must 
be  strong  in  order  to  mobilize  the  joint. 

Action  and  Uses  of  Therapeutic  Exercise 

Whereas  an  ordinary  locomotive  may  be  only  4  per  cent,  efficient,  the 
human  Body  is  much  more  efficient;  it  varies  in  efficiency  from  about  20 
to  40  per  cent.'.  When  a  muscle  is  subjected  to  stress,  it  will  respond  by 
increase  in  tension.  This  is  known  as  the  "stretch  reflex".  A  muscle, 
which  is  held  in  a  shortened  position,  tends  to  become  tonically  shortened; 
one,  which  is  kept  in  an  elongated  position,  tends  to  become  permanently 
stretched. 

Passive  movements  at  first  produce  little  change  in  the  rate  of  the 
pulse,  but  as  the  part  becomes  fatigued,  there  may  be  a  slow  rise  in 
the  rate  of  the  pulse.  On  voluntary  contraction  of  muscles  the  rate  of  the 
pulse  increases  more  rapidly.  The  extent  of  the  increase  in  cardiac  rate 
depends  to  a  great  extent  on  the  physical  condition  of  the  subject. 
Although  the  pulse  rate  of  an  untrained  individual  may  increase  25  to  40 
beats  per  minute  from  moderate  volitional  exercise,  this  can  be  considered 
a  normal  response  to  moderate  exercise.  The  trained  athlete's  cardiac 
rate  will  increase  very  little,  because  his  heart  responds  to  increased  effort 
by  increase  in  the  stroke  volume  of  the  heart  rather  than  by  increase  in  the 
rate  of  contraction.  It  has  not  been  proved,  however,  that  this  increase  in 
the  stroke  volume  is  any  easier  on  the  heart  itself  than  is  an  increase  in  rate. 

Vol.  I.  941 


8io  (54)  PHYSICAL   MEDICINE 

The  cardiac  rate  of  the  normal  individual  should  return  to  normal 
levels  within  a  half  hour  following  moderate  exercise.  If  the  exercise 
has  been  exhausting,  the  rate  of  the  pulse  may  remain  accelerated  for 
several  hours.  Because  of  these  facts  it  becomes  obvious  that  measure- 
ments of  the  rate  of  the  pulse  and  the  length  of  time  that  the  pulse  re- 
mains accelerated  are  good  indexes  of  the  amount  of  exercise  which  a 
patient  can  tolerate. 

Best  and  Taylor^  have  estimated  that  the  fiow  of  blood  through  active 
muscles  may  be  twenty  or  more  times  as  great  as  the  fiow  during  rest. 
During  exercise  a  much  greater  portion  of  the  capillary  bed  is  supplied 
with  blood.  Both  arterial  and  venous  blood  pressures  are  increased  during 
exercise.  The  part,  which  active  exercise  takes  in  assisting  circulation,  is 
appreciated  insufficiently  by  many  physicians,  and  the  deleterious  effects 
of  prolonged  rest  often  are  overlooked. 

Exercise  tends  to  increase  general  metabolic  activity.  Even  very 
slight  exercises,  such  as  writing,  may  increase  the  metabolic  rate  25  to  50 
per  cent,  above  the  basal  level.  Vigorous  exercise  may  increase  the 
metabolic  rate  to  ten  to  twenty  times  the  basal  level. 

It  is  impossible  within  the  limits  of  this  chapter  to  describe  in  detail 
the  exercises  which  should  be  employed  for  various  diseases.  Therefore, 
when  possible,  I  shall  refer  the  reader,  who  wishes  detailed  exercises,  to 
suitable  sources  of  information. 

Corrective  exercises  may  be  extremely  useful  in  the  management  of 
postural  deformities.  The  physician,  who  is  interested  in  this  subject, 
should  refer  to  the  report  of  the  Subcommittee  on  Orthopedics  and  Body 
Mechanics  of  the  White  House  Conference  on  Child  Health  and  Pro- 
tection^ and  to  the  textbooks  by  Gold th wait  and  his  associates^  and  by 
Phelps  and  Kiphuth''  which  deal  fully  with  this  important  problem. 
Elsewhere^  I  have  described  the  exercises  employed  at  the  Mayo  Clinic 
for  treatment  of  weakness  and  pronation  of  the  feet  as  well  as  exercises 
for  postural  backache,  lumbar  lordosis  and  scoliosis.  Kleinberg*  has 
written  an  excellent  monograph  on  scoliosis. 

One  of  the  most  interesting  recent  developments  in  the  field  of  thera- 
peutic exercise  concerns  its  employment  for  the  control  of  some  of  the 
symptoms  of  bronchial  asthma.  The  Asthma  Research  Council  of  King's 
College,  London^,  has  published  an  excellent  small  booklet,  which  is  well 
illustrated  and  inexpensive,  and  which  can  be  employed  by  the  patient 
as  an  instruction  manual  while  learning  the  exercises.  Livingstone  and 
Gillespie^"  and  Bray^^  have  reported  favorably  concerning  the  efficacy  of 
these  exercises  in  relieving  some  of  the  distress  of  the  asthmatic  attacks 
and   even   in   aborting   the  attacks.     These  exercises  for  asthma  are  di- 

VoL.  I.  941 


ACTION  AND   USES  8io  (55) 

rected  especially  toward  teaching  the  patient  to  make  a  prolonged  volun- 
tary expiratory  effort  and  to  develop  ability  in  abdominal  breathing. 

Exercises  play  an  extremely  important  part  in  the  management  of  the 
residual  effects  of  poliomyelitis.  The  physician  desiring  detailed  informa- 
tion concerning  such  exercises  should  consult  the  excellent  small  and  in- 
expensive booklets  on  this  subject  by  the  Kendalls^-  and  by  Greteman  and 
Jackson^^  as  well  as  the  free  booklet  by  Stevenson'*.  Other  valuable 
communications  on  this  subject  include  those  of  Hansson'^,  Legg  and 
Merrill'^  and  Lovett'^ 

Another  group  of  patients,  who  have  been  neglected  much,  and  who 
receive  great  benefit  from  prolonged  training  in  corrective  exercise,  is  the 
throng  of  children  suffering  from  cerebral  palsy.  Because  of  the  limited 
facilities  which  are  available  for  proper  training  of  these  unfortunate 
youngsters,  and  it  has  been  estimated  that  there  are  ro8  treatable  cases 
of  cerebral  palsy  for  each  200,000  population,  it  often  becomes  necessary 
for  a  parent  to  carry  on  the  training  of  the  child  at  home.  I  have  found 
that  Girard's  excellent  monograph'*  is  a  valuable  guide  for  such  parents. 
Other  books  to  which  these  parents  can  refer  include  the  ones  by  Fischel'''', 
Rogers  and  Thomas'-"  and  Abele  and  Greteman-'.  In  addition  every  pa- 
tient with  cerebral  palsy  can  get  a  great  deal  of  inspiration  by  reading 
the  semibiographical  book  by  Earl  R.  Carlson'",  himself  a  sufferer  from 
cerebral  palsy,  who  has  devoted  his  career  as  a  physician  to  the  treatment 
of  "the  severely  birth-injured". 

Coulter''^  has  described  a  set  of  modified  Frenkel  co-ordination  exercises 
which  can  be  employed  to  advantage  in  the  treatment  of  combined 
sclerosis  and  tabes  dorsalis.  He  has  given  also  an  excellent  description  of 
the  proper  methods  of  employing  exercise  in  cardiac  diseases  and  in  the 
management  of  hemiplegia.  Sever-'*  has  presented  detailed  information 
concerning  the  employment  of  corrective  exercises  for  obstetrical  paralysis. 
Elsewhere  F  have  given  a  description  of  exercises  of  individual  joints 
following  trauma. 

Occupational  therapy  is  a  form  of  therapeutic  exercise  and  anyone  in- 
terested in  this  extensive  field  of  therapy  should  refer  to  the  writings  of 
Davis  and  Dunton-^,  Dunton'-^,  Mock"  and  Mock  and  Abbey-^. 

To  summarize  concerning  the  uses  of  therapeutic  exercise,  one  may  say 
that  general  postural  exercises  are  required  in  the  management  of  such 
conditions  as  scoliosis,  kyphosis  and  lordosis.  Postural  exercises  may 
benefit  or  may  prevent  orthostatic  albuminuria,  postural  backache, 
chronic  postural  strain,  exhaustion  states  or  functional  decompensation  of 
the  muscles  of  the  back.  Foot  postural  exercises  may  be  useful  in 
treatment  of  pronation  of  the  feet  or  in  treatment  of  breaking  down  of 

Vol.  I.  941 


8ro  (56)  PHYSICAL   MEDICINE 

the    longitudinal    or    transverse    arches    of    the    feet.      Exercises    may    be 
valuable  in  overcoming  muscular,  tendinous  or  fascial  contractures. 

Among  the  medical  conditions,  which  often  can  be  benefited  by  ex- 
ercises of  certain  types,  can  be  mentioned  asthma,  arthritis,  cardiac  dis- 
ease, cerebral  palsy,  combined  sclerosis,  hemiplegia,  poliomyelitis  and 
tabes  dorsalis.  Among  the  surgical  lesions,  which  can  be  helped  by 
various  types  of  exercise,  can  be  mentioned  contusions,  sprains,  strains, 
dislocations,  fractures,  amputations,  peripheral  nerve  lesions  and  obstetri- 
cal paralysis.  Exercises  of  the  legs  may  prevent  postoperative  thrombosis, 
and  abdominal  exercises  can  be  employed  to  strengthen  the  muscles 
following  pregnancy  or  prior  to  herniorrhaphy. 

Contraindications  to  the  Employment  of  Therapeutic  Exercise 

There  are  few  contraindications  to  the  use  of  exercise  because  activity 
is  a  normal  state.  In  some  instances,  however,  exercises  are  overdone  or 
are  performed  incorrectly.  Following  injury  to  certain  joints,  particularly 
the  elbow,  if  exercise  is  started  too  early,  or  if  passive  movement  is  applied 
too  vigorously,  further  trauma  and  eventually  ankylosis  may  result. 

Patients,  who  have  neurocirculatory  asthenia,  or  "effort  syndrome", 
tolerate  exercise  poorly.  In  the  presence  of  cardiac  disease  exercise,  al- 
though not  usually  contraindicated,  should  be  employed  only  with  great 
caution  and  after  proper  testing  of  the  tolerance  of  the  patient  to  exercise. 

If  employed  injudiciously,  exercise  may  precipitate  hemorrhage,  loosen 
emboli  or  cause  similar  disastrous  results. 

Summary  of  Data  on  Therapeutic  Exercise 

Corrective  or  therapeutic  exercise  now  is  applied  or  directed  usually 
by  skilled  technicians  working  under  direct  medical  supervision.  Exercise, 
if  at  all  strenuous,  should  be  prescribed  only  after  a  careful  examination 
of  the  cardiovascular  system.  Such  exercise  is  useful  in  many  diseases 
and  is  an  indispensable  part  of  modern  therapy. 

BIBLIOGRAPHY  OF  THERAPEUTIC   EXERCISE 

1.  MACKENZIE,  C:    The  Action  of  Muscles  Including  Muscle  Rest  and  Muscle 

Re-education,  Ed.  2,  Hoeber,  New  York,   1930. 

2.  SCHNEIDER,   E.   C:    Physiology  of  Muscular  Activity,   Saunders,   Philadel- 

phia,  1933- 

3.  BEST,  C.  H.  and  TAYLOR,  N.  B.:    The  Physiological  Basis  of  Medical  Prac- 

VOL.   I.    941 


BIBLIOGRAPHY  8io  (57) 

tice;  a  University  of  Toronto  Text  in  Applied  Physiology,  Ed.  2,  Williams 
and  Wilkins,  Baltimore,  1939. 

4.  REPORT     OF     SUBCOMMITTEE     ON     ORTHOPEDICS     AND     BODY 

MECHANICS:  Body  Mechanics;  Education  and  Practice,  White  House 
Conference  on  Child  Health  and  Protection,  The  Century  Company, 
New  York,   1932. 

5.  GOLDTHWAIT,  J.  E.,  BROWN,  L.  T.,  SWAIM,  L.  T.  and  KUHNS,  J.  G.: 

Body  Mechanics  in  the  Study  and  Treatment  of  Disease,  Lippincott,  Phil- 
adelphia,  1934. 

6.  PHELPS,  W.  M.  and  KIPHUTH,  R.  J.  H.:    The  Diagnosis  and  Treatment  of 

Postural   Defects,  Charles  C.  Thomas,  Springfield,   Illinois,    1932. 

7.  KRUSEN,  F.  H.:    Physical  Medicine,  Saunders,  Philadelphia,  1941. 

8.  KLEINBERG,  S.:    Scoliosis;    Rotary  Lateral  Curvature  of  the  Spine,  Hoeber, 

New  York,   1926. 

9.  ASTHMA   RESEARCH   COUNCIL,  KING'S  COLLEGE,  LONDON:    Phys- 

ical Exercises  for  Asthma,  Ed.  3,  Chicago  Medical  Book  Company,  Chi- 
cago,  1939. 

10.  LIVINGSTONE,  J.  L.  and  GILLESPIE,  M.:   The  value  of  breathing  exercises 

in  asthma.  Lancet,  1935,  II,  705. 

11.  BRAY,   G.   W.:     Recent   Advances   in   Allergy    (Asthma,    Hay-fever,    Eczema, 

Migraine,  etc.),  Ed.  2,  Blakiston,  Philadelphia,   1934. 

12.  KENDALL,  H.  O  and  KENDALL,  F.  P.:    Care  during  the  recovery  period  in 

paralytic  poliomyelitis.  Public  Health  Bulletin  242,  United  States  Treasury 
Department,  Public  Health  Service,   1938. 

13.  GRETEMAN,  T.  J.  and  JACKSON,  R.  B.:^  Care  of  Infantile  Paralysis  in  the 

Home;    a  Handbook  for  Parents,  John  S.  Swift  Co.,  Inc.,  St.  Louis,  1938. 

14.  STEVENSON,  J.  L.:    The  Nursing  Care  of   Patients  with  Infantile  Paralysis, 

The  National  Foundation  for  Infantile  Paralysis,  New  York,   1940. 

15.  HANSSON,  K.  G.:    After-treatment  of  poliomyelitis.  Jour.  Am.  Med.  Assoc, 

1939,  CXIII,  32. 

16.  LEGG,  A.  T.  and  MERRILL,  J.  B.:    Physical   therapy  in   infantile   paralysis, 

Reprinted  from  Principles  and  Practice  of  Physical  Therapy,  Prior,  Hagers- 
town,  Maryland,   1932. 

17.  LOVETT,    R.   W.:    The  Treatment  of   Infantile   Paralysis,    Ed.   2,   Blakiston, 

Philadelphia,  1917. 

18.  GIRARD,    P.   M.:    The  Home  Treatment  of  Spastic   Paralysis  Written  in  a 

Simple,  Practical  Way  with  Man>'  Detailed  Drawings,  Lippincott,  Phila- 
delphia, 1937. 

19.  FISCHEL,    M.    K.:     The   Spastic   Child;    a   Record  of   Successfully  Achieved 

Muscle  Control  in  Little's  Disease,  Mosby,  St.  Louis,   1934. 

20.  ROGERS,   G.   G.   and   THOMAS,   L.   C:    New   Pathways  for  Children   with 

Cerebral  Palsy,  Macmillan,  New  York,  1935. 

21.  ABELE,  J.  F.  and  GRETEMAN,  T.  J.:    Care  of  the  Spastic  Paralytic  Child 

in  the  Home;    a  Handbook  for  Parents,  Children's  Hospital,   Iowa  City, 
Iowa,  1938. 
Vol.  I.  941 


8io  (58)  PHYSICAL   MEDICINE 

22.  CARLSON,  E.  R.:    Born  That  Way,  John  Day  Company,  New  York,  1941. 

23.  COULTER,  J.  S. :    The  use  of  therapeutic  exercise  in  internal  medicine  and  in 

neurology,  in  Principles  and   Practice  of  Physical  Therapy,  Vol.   Ill,  pp. 
1-68,  Prior,  Hagerstown,  Maryland,  1934. 

24.  SEVER,  J.  VV. :    The   physical    therapy   of  obstetrical   paralysis,   in  Principles 

and   Practice  of  Physical  Therapy,  Vol.  II,  pp.   1-26,   Prior,  Hagerstown, 
Mar>dand,  1934. 

25.  DAVIS,  J.  E.  and  DUNTON,  W.  R.,  Jr.:    Principles  and  Practice  of  Recrea- 

tional Therapy  for  the  Mentally   111,   A.   S.   Barnes  and  Company,   New 
York,  1936. 

26.  DUNTON,  \V.   R.,  Jr.:    Occupational   therapy,   in    Principles  and   Practice  of 

Physical  Therapy,  Vol.  I,  pp.  1-48,  Prior,  Hagerstown,  Maryland,  1934. 

27.  MOCK,  H.  E. :    Reconstructive  surgery  and  functional  recreation,  in  Principles 

and  Practice  of  Physical  Therapy,  Vol.  II,   pp.    1-12,    Prior,    Hagerstown, 
Maryland,   1934. 

28.  MOCK  H.   E.  and  ABBEY,  M.  L.:    Occupational  therapy,  in    Handbook  of 

Physical  Therapy,  Ed.  3,  pp.  165-178,  American  Medical  Association  Press, 
Chicago,   1939. 

Sept.  I,  1941. 


Vol.  I.  941 


CHAPTER  XXII 
THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

By  L.  G.  ROWNTREE 

Table  of  Contents 

Introduction .       .811 

The  Historical  Evolution  of   Medical   Doctrines 813 

Present-Day  Forms  of  Therapy .827 

Factors  Responsible  for  Progress  in  Therapy 831 

1.  Advancement  of  Science  and  Progress  of   Medicine       .       .     832 

2.  The  Development  of   Pharmacology 834 

3.  The  Chemical  Basis  of  Pharmacology 840 

Instances  of  Chemical  Constitution  Controlling  Pharma- 
cological Action 847 

4.  Specific  Chemotherapy  and  Experimental  Therapy     .       .       .     859 

Specific  Chemotherapy  of  Trypanosomiasis   ....  860 

Specific  Chemotherapy  of   Spirilla 871 

Specific  Chemotherapy  of   Spirochetes    (Syphilis)             .  874 
Specific   Chemotherapy   in    Protozoal   and   Bacterial    Dis- 
eases   Contrasted 875 

5.  Infection  and   Antiseptics 876 

6.  The  Role  Played  by  Glands  of   Internal  Secretion    .        .       .  883 

7.  Treatment  Based  on  a  Functional  Conception  of  Disease       .  905 

Myocardial    Insufficiency 905 

8.  Medical    Organization 9^9 

What  Is  Needed  for  the  Advance  of  Therapy 920 

Introduction 

To  the  thinking  physician  treatment  does  not  consist  merely  in  apply- 
ing measures  of  relief.  The  essence  of  treatment  consists  :  in  recognizing 
the  pathological  process ;  in  understanding  its  nature,  its  cause,  the 
mechanism  involved  in  its  production  and  in  the  development  of  its 
clinical  manifestations;  in  knowing  the  character,  extent,  and  probable 
outcome  of  the  resulting  functional  and  morphological  changes;  in 
valuing  correctly  the  significance  of  clinical  and  laboratory  findings;  in 
ascertaining  the  indication  for,  in  knowing  the  mode  of  action  of,  and  the 
most  effective  methods  of  applying  measures  for  its  prevention,  abortion, 
amelioration,  or  cure. 

811 


8i2      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

A  correct  diagnosis  is  the  first  essential  to  treatment.  Direct  and 
specific  therapy  begins  with  diagnosis,  failing  which,  general  or  palliative 
measures  only  are  possible.  It  is  to  be  recognized  that,  with  or  without 
diagnosis,  cures  result  at  times,  the  work  of  nature,  not  of  medicine. 

Doctrines  control  therapy.  Treatment  is  good  or  bad  according  to 
whether  doctrines  are  true  or  false.  These  are  subject  to  evolution. 
Verified  and  established  they  constitute  the  science  of  medicine.  Their 
relation  to  treatment  is  twofold.  They  concern  the  nature  and  mechanism 
of  pathological  processes  on  the  one  hand,  and  on  the  other,  the  mode  of 
action  of  measures  of  relief. 

In  treatment  there  are  two  fundamentally  different  points  of  view  of 
disease;  viz.,  the  morphological  and  the  functional.  Both  are  important. 
The  former  as  pathology  has  dominated  the  field  of  medicine.  The  latter, 
pathological  physiology,  is  more  difficult  to  acquire,  but  is  essential  to 
therapy,  since,  generally  speaking,  drugs  affect  function  rather  than  form. 
Not  until  the  physician  sees  a  deranged  function  as  well  as  a  lesion  will 
he  become  a  master  of  treatment.  Recognition  of  derangement  of  func- 
tion presupposes  a  knowledge  of  normal  function.  Physiology,  therefore, 
becomes  the  basis  or  starting-point  of  therapy,  the  diagnosis  incorporat- 
ing a  physio-pathological  conception  of  disease. 

Pharmacology  deals  with  the  action  of  drugs.  Though  it  be  youthful, 
it  is  already  a  vigorous  science.  It  brings  with  it  to  the  bedside  the  tools 
of  science;  investigation,  experimentation,  standards,  exactness  in  meas- 
urement, observation,  and  analysis.  It  necessitates  and  hence  develops 
critical  judgment.  It  reveals  facts  concerning  changes  in  bodily  function 
wrought  by  the  action  of  drugs,  the  mechanism  whereby  these  changes 
are  effected,  and  not  infrequently  uncovers  physiological  processes  previ- 
ously unrecognized.  It  yields  quantitative  results.  One  of  the  great 
weaknesses  of  drug  therapy  today  is  the  lack  of  quantitative  determina- 
tion of  results.  Many  drugs  are  threshold  bodies,  that  is,  they  must  reach 
certain  levels  in  the  body  before  they  exercise  beneficial  effects.  On  the 
other  hand,  the  majority  of  them,  in  the  event  of  overdosage,  lead  to 
untoward  effects  resulting  in  the  nullifying  of  therapeutic  action,  to 
exacerbations  of  the  original  symptoms,  or  in  the  appearance  of  other 
untoward  clinical  manifestations. 

In  practice  the  end  may  be  attained  by  various  measures  acting  in 
different  ways.  In  order  to  obtain  maximum  results  familiarity  with  the 
mode  of  action  of  the  remedy  is  essential,  and  a  treatment  must  be 
employed  which  combats  the  pathological  process  as  near  its  source  as 
possible,  preferably  by  one  which  eradicates  the  cause. 

Health  is  the  normal  balance  in  physiological  functions.  In  the 
organism    factors   of   safety   are   large.      Nature   has   provided   many 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES  813 

defenses  against  disease  and  is  ingenious  in  meeting  difficulties  and 
dangers.  Vicarious  activity  and  sharing  of  function  is  resorted  to 
repeatedly.  Successively  or  simultaneously  several  lines  of  defense  may 
be  called  into  play  and  must  be  overcome  before  a  vital  function  is 
actually  endangered.  Where  the  cause  is  beyond  attack,  treatment  may 
so  affect  this  balance  that,  despite  an  irremovable  cause  and  an  all  but 
exhausted  reserve,  function  is  maintained  and  life  goes  on  without  dis- 
abling symptoms  and  perhaps  without  serious  restrictions. 

The  requisites  of  treatment  are:  (i)  correct  diagnosis;  (2)  a  true 
conception  of  the  cause  and  nature  of  the  derangement;  (3)  familiarity 
with  the  manner  in  which  the  derangement  can  be  corrected;  and  (4) 
knowledge  concerning  the  means  whereby  this  may  be  effected. 

These  appear  simple  matters,  withal,  but  they  are  the  revelations  of 
succeeding  ages — the  handiwork  of  evolving  science.  Now,  as  in  the 
days  of  Hippocrates,  "  Experience  is  fallacious  and  judgment  difficult." 

Oliver  Wendell  Holmes  says,  "  The  debris  of  broken  systems  and 
exploded  dogmas  form  a  great  mound,  a  Monte  Testaccio  of  the  shards 
and  remnants  of  old  vessels  which  once  held  human  beliefs.  If  you  take 
the  trouble  to  climb  on  top  of  it,  you  will  widen  your  horizon,  and  in 
these  days  of  special  knowledge  your  horizon  is  not  likely  to  be  any  too 
wide."  We  can,  with  profit,  consider  the  evolution  of  medical  doctrines 
underlying  the  treatment  of  the  past,  study  the  methods  and  beliefs  of  our 
forefathers,  observe  their  mistakes  and  successes,  and  the  causes  of  each, 
and  compare  in  these  respects  the  medicine  of  the  past  with  that  of  to-day. 

The  Historical  Evolution  of  Medical  Doctrines 

Primitive  man  found  himself  confronted  with  functional  disabilities. 
He  suffered,  not  from  disease,  but  from  symptoms;  headache,  jaundice, 
chills,  blindness,  or  weakness.  The  cause,  nature,  or  the  significance  of 
the  symptoms,  the  underlying  disease,  the  nature  of  the  derangement, 
prognosis,  and  the  treatment  were  all  unknown.  Doctors,  textbooks,  and 
medicine  were  not  in  existence.  Biology,  anatomy,  physics,  chem- 
istry, physiology,  pathology,  pharmacology,  and  therapeutics  were  still 
undreamed  of.  Education,  mental  training,  observation,  logic  and 
experimentation,  drugs  and  instruments  were  all  lacking.  When  sick 
he  had  recourse  merely  to  his  fellowmen,  to  the  animal  world  about  him, 
and  to  himself.  He  could  observe,  listen,  imitate,  speculate,  imagine,  and 
obey.  He  already  believed  in  a  supernatural  being  who  was  responsible 
for  all  he  could  not  understand.  Surrounded  by  ignorance  and  super- 
stition, he  was  the  recipient  of  kind-hearted,  well-meaning  advice  or 
treatment,  born  of  actual  experience  in  some  instances,  more  often  of 


8i4     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

pretense  of  knowledge  assumed  for  gain  or  prestige.  He  desired  relief 
from  sufferings  and  restitution  to  health.  He  followed  his  instincts  or 
natural  inclinations,  usually  adopting  the  expectant  principle  of  treatment, 
lying  at  rest  awaiting  recovery.  This  failing,  he  consulted  with  his 
fellowman  and  adopted  his  advice  or  appealed  to  the  supreme  being  for 
relief.  In  the  event  of  recovery,  he  sang  the  praises  of  the  treatment 
and  its  author  or  lifted  his  voice  in  thanks  to  the  Almighty. 

The  savage's  conception  of  disease  is  essentially  spiritualistic.  Super- 
natural agencies  are  of  various  kinds  :  ( i )  independent  devil-born  demons 
of  disease;  (2)  departed  spirits,  ghosts,  or  spirits  of  the  dead;  (3)  spirits 
of  slain  animals;  (4)  human  enemies  who  act  through  their  own  super- 
natural powers  by  casting  spells  or  indirectly  through  one  or  other  of 
the  types  of  spirits  already  mentioned;  and  (5)  spirits  acting  through 
the  direction  of  the  Almighty  to  aid  in  the  administration  of  punishment 
or  the  wreaking  of  vengeance  on  man  for  his  manifold  shortcomings  and 
sins.  The  latter  group  is  the  most  important,  since  in  them  belief  still 
exists  to  some  extent  even  among  civilized  nations,  and  they  were 
responsible  to  a  large  extent  for  the  sacerdotal  trend  of  early  medicine. 

According  to  Withington  (^)  three  methods  of  procedure  have  been 
found  efifective  by  the  savage  medicine  man  in  combating  supernatural 
agencies  of  disease:  (i)  rendering  the  body  an  unpleasant  abode  for  the 
intruding  spirit  through  squeezing,  beating,  starving,  or  fumigating  it, 
or  through  the  use  of  nauseating  drugs  which  result  in  vomiting;  (2) 
offering  the  spirit  a  more  pleasant  abode,  for  instance,  the  demon  of 
jaundice  can  be  enticed  into  a  yellow  canary,  and  that  of  ague  into  a 
cold,  clammy  frog;  (3)  the  intervention  of  other  spiritual  forces.* 
The  first,  or  what  may  be  considered  as  expulsion  by  violence,  is  repre- 
sented by  emetics  and  massage;  the  second,  or  wily  seduction,  finds 
expression  in  the  "  signatures  "  of  the  middle  ages  and  perhaps  in  the 
"  similia  similibus  curantur  "  of  our  day;  and  the  third,  or  the  inter- 
vention of  other  spiritual  forces,  is  largely  responsible  for  the  role  played 
by  the  priesthood  in  the  history  of  medicine. 

Our  knowledge  of  the  medicine  of  uncivilized  or  early  civilized  man 
is  derived  largely  through  ancient  writings  or  their  translations,  through 
folklore,  through  the  tracing  back  of  peculiar  customs,  and  through 
investigations  of  recent  date  of  peoples  still  uncivilized  (Madagascar, 
Tahiti,  Indians  of  North  and  South  America). 

*  This  idea  also  resulted  in  the  belief  in  witchcraft,  wherein  the  same  power  was 
used  for  purposes  other  than  good. 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES   815 

Egyptian  Medicine 

This  is  revealed  through  the  study  of  tombs,  pyramids,  and  ancient 
writings.  From  the  tombs  we  learn  of  Sekhet'-enanch,  the  first  physician 
known  to  history,  who  lived  about  3000  or  possibly  3500  B.C.,  and  of 
the  existence  in  his  day  of  the  lancet  and  of  a  cupping  instrument.  But 
our  chief  knowledge  of  Egyptian  medicine  is  derived  through  the  Ebers 
Papyrus,  which  was  written  about  1550  B.C.  This  is  mainly  a  collection 
of  receipts,  and  from  it  we  learn  something  of  the  therapy  of  early  Egypt, 
thus  "  Schepen  "  (probably  the  poppy)  is  useful  to  soothe  crying  babies. 
"  Against  all  kinds  of  witchcraft,  a  large  beetle,  cut  off  his  head  and 
wings,  boil  him,  put  him  in  oil  and  apply  to  the  part.  Then  cook  his 
head  and  wings,  put  them  in  serpent's  fat,  warm  it,  let  the  patient  drink 
it."  "  To  make  the  skin  of  the  face  smooth,  soak  meal  in  spring  water. 
Let  her  wash  her  face  daily  and  then  apply  the  meal."  "  To  keep  away 
mice,  smear  everything  possible  with  cat's  fur."  Pills,  potions,  inunc- 
tions, inhalations,  and  plasters  were  all  used  in  these  days. 

It  also  contains  some  remarkable  passages  relating  to  diagnosis.  One 
reference  to  the  circulatory  system  is  particularly  interesting :  "The 
vessels  are  said  to  run  in  pairs  .  .  .  and  to  contain  not  only  blood, 
but  air,  water,  milk,  and  other  fluids."  In  the  doctrine  of  the  heart  as 
the  center  of  the  vascular  system,  and  in  the  importance  attributed  to  the 
pulse,  the  Egyptians  were  in  advance  of  Hippocrates.  "If  the  physician 
place  his  fingers  on  the  head,  neck,  hands,  arms,  feet,  or  body,  every- 
where he  will  find  the  heart  (i.e.  the  pulse),  for  the  vessels  go  to  all 
parts."  * 

The  Berlin  Papyrus,  which  is  of  somewhat  later  date,  contains  many 
prescriptions  and  abounds  in  incantations.  More  than  the  Ebers  Papyrus 
it  emphasizes  the  supernatural  origin  of  disease. 

Egyptian  medicine,  just  as  Egypt  itself,  marked  time  for  nearly  3,000 
years.  In  fact,  judging  from  the  relative  popularity  and  success  of 
Egyptian  and  Greek  physicians  at  the  time  of  Hippocrates,  and  also 
later,  the  Egyptian  physicians  appeared  to  be  hopelessly  outclassed. 

Hindu  Medicine 

Our  knowledge  of  Hindu  medicine  is  revealed  through  the  Vedas  or 
"  Works  of  Wisdom."  The  4th  or  Atharva  Veda,  written  about  700 
B.C.,  and  later  supplementary  Vedas,  are  the  most  important  from  the 
standpoint  of  medicine.     From  them  we  learn  of  the  medical  work  of 

*  From  Withington's  (1)  "Medical  History  from  the  Earliest  Times."  To 
Withington  the  author  is  indebted  for  most  of  the  historical  sketch  here  presented. 
Garrison  (i)   and  Baass  {^ )  have  also  been  freely  consulted. 


8i6     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

Charaka  and  Susruta,  which  indicate  that  the  Hindu  medicine  of  300  B.C. 
to  750  A.D.  (the  period  of  Buddhist  predominance)  compares  favorably 
with  the  contemporary  Hellenic  medicine.  The  Hindu  medicine  con- 
tributed much  to  surgery,  and  to  organized  medical  effort  such  as  medical 
teaching,  army  sanitation,  hospitals,  and  asylums  for  the  blind  and  lame. 
Surgery  was  favored  rather  than  medicine,  thus  by  Susruta  new 
noses  were  created  from  cheek  and  forehead  flaps,  supraorbital  nerves 
were  sectioned  in  neuralgia,  even  laparotomies  were  suggested.  In 
writing  of  his  calling,  he  says,  "  Surgery  is  the  first  and  highest  division 
of  the  healing  art,  least  liable  to  fallacy,  pure  in  itself,  perpetual  in  its 
application,  the  worthy  product  of  heaven,  the  source  of  fame  on  earth." 

Early  Greek  Medicine 

Hippocrates  was  the  founder  of  Greek  medicine  and  of  medicine  in 
general.  However,  prior  to  his  time  medicine  had  made  considerable 
progress.  Homer's  account  of  medicine  relates  mostly  to  surgery,  but 
he  introduces  us  to  drugs  "  pharmakon,"  which  in  the  "  Iliad  "  refers  to 
remedies  externally  applied  and  in  the  "  Odyssey  "  to  either  poisons  or 
charms.  He  also  intimates  that  knowledge  of  drugs  constitutes  a 
criterion  for  judging  the  ability  of  a  physician.  In  his  time  medicine  and 
surgery  were  definitely  distinguished,  the  distinction  having  been  made 
primarily  by  ^sculapius;  for  Machaon,  one  son,  was  endowed  with 
skilled  hands  to  draw  out  darts  and  make  incisions,  while  to  Podalirius, 
the  other,  was  given  all  cunning  to  find  out  things  invisible  and  to  "  cure 
that  which  healed  not."  In  Homer's  day  "  incubation  "  flourished  before 
the  altars  of  the  Asclepieia  or  temples  of  ^sculapius.  The  patient,  after 
priestly  preparation,  lay  down  to  sleep  before  the  altar,  whereupon  was 
revealed  to  him  by  dreams  or  through  the  priests  those  things  necessary 
for  recovery.    In  this  way  many  miracles  were  wrought. 

Empedocles,  b.c.  490430,  is  also  worthy  of  mention  because  he  laid 
the  foundation  for  the  humeral  pathology  of  Hippocrates,  and  introduced 
the  four  elements  into  medical  philosophy.  Withington  (^)  presents  a 
fragment  of  one  of  his  poems  "  On  Nature." 

"  Listen  first,  while  I  sing  the  fourfold  root  of  creation, 
Fire,  and  water,  and  earth,  and  the  boundless  height  of  the  ether. 
For  thereupon  is  begotten  what  is,  what  was,  and  what  shall  be." 

Hippocrates  adopted  this  idea  of  "  fire,  water,  earth,  and  air,"  but 
enlarged  upon  it.  He  considered  heat,  cold,  dryness,  and  moisture  as 
four  corresponding  qualities,  and  blood,  phlegm,  yellow  bile,  and  black 
bile  as  the  four  corresponding  bodily  juices  or  humors.  Each  humor 
had  its  own  seat:  thus  for  the  blood,  the  heart;  for  phlegm,  the  brain; 
for  yellow  bile,  the  liver ;  and  for  black  bile,  the  spleen.    Health  was  unim- 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES   817 

paired  so  long  as  each  humor  remained  in  its  own  place  and  in  its  proper 
proportion  relatively,  but  disease  resulted  from  disproportionate  amounts 
and  from  an  element  out  of  its  proper  sphere.  In  this  conception  quan- 
tities and  interdependence  of  function  are  obviously  recognized.  In  other 
words,  Hippocrates  conceived  organization  in  the  body,  but  his  false 
doctrines  of  pathology  precluded  the  possibility  of  a  scientific  foundation 
for  medicine. 

Early  Greek  medicine  was  not  entirely  sacerdotal.  Priests,  philoso- 
phers, and  physical  trainers  practiced  medicine  as  well  as  physicians 
proper.  But  whereas  the  physicians  practiced  the  healing  art,  the  priest 
corresponded  to  the  mental  or  faith  healers,  philosophers  to  medical 
scientists  or  physiologists,  and  the  physical  trainers  to  bone-setters  of 
later  centuries.  The  physicians  and  the  philosophers,  however,  were 
responsible  for  medical  progress. 

Hippocrates,  the  father  of  medicine,  born  460  b.c,  flourished  in  the 
golden  age  of  Pericles,  a  contemporary  of  the  most  brilliant  group  of 
men  known  to  history.  He  w^as  a  practicing  physician  and  a  philosopher. 
By  virtue  of  his  dual  interest,  he  clearly  separated  the  two.  His  greatest 
contribution  to  medicine  was  his  rejection  of  the  supernatural.  In  this 
he  was  influenced  to  some  extent  by  his  environment,  for  at  that  time 
the  Greeks  were  in  a  transition  period,  falling  away  generally  from  their 
belief  in  mythology.  That  his  rejection  of  the  supernatural  resulted  in 
his  other  contributions  to  medicine  is  within  the  realm  of  possibility,  for 
what  is  more  natural  than  that  one,  needing  support  in  his  anomalous 
position  as  champion  of  natural  causes  for  disease,  should  undertake  to 
prove  the  cause,  nature,  and  course  of  disease? 

In  his  study  of  disease  he  emphasized  the  necessity  of  accurate  obser- 
vation, describing  the  facies  and  the  splash  bearing  his  name.  He  made 
clear,  concise,  clinical  records,  more  than  forty  of  which  are  preserved, 
and  from  which  it  is  possible  in  some  instances  to  make  diagnoses. 
Diseases  were  considered  in  their  entirety,  the  course  and  final  outcome 
being  noted.  He  recorded  his  deaths,  which  were  relatively  numerous. 
He  was  the  first  to  properly  value  prognosis,  stating  that  though  cure 
was  the  most  important  consideration,  it  was  well  for  the  physician  to 
be  able  to  predict  the  outcome  of  any  illness.  His  methods  were  those  of 
science,  accurate  observation,  careful  records,  interest  sustained  to  a 
conclusion,  in  an  attempt  to  predict  the  outcome  from  the  facts  available. 

Of  his  treatment  little  is  known  except  that,  recognizing  the  limitation 
of  diagnosis  and  of  therapy,  he  insisted  on  considering  the  individual 
rather  than  the  disease  and  above  all  things  on  doing  no  harm.  Treat- 
ment to  him  consisted  of  assisting  nature,  for  his  belief  was  strong  in 
the  "  vis  medicatrix  naturae,"  environment,  diet,  bowels,  sleep  and  all 


8i8     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

the  natural  functions  receiving  appropriate  attention.  Purgatives  and 
bleeding  he  used  most  frequently.  Treatment  was  individualistic,  the 
patient's  comfort,  feelings,  and  wishes  being  consulted  and  considered  as 
far  as  possible. 

His  aphorisms  alone  would  have  sufficed  to  bring  his  name  down 
through  the  ages,  revealing  his  philosophical  outlook  on  life  and  his 
great  store  of  wisdom.  Hippocrates  not  only  stands  as  the  father  of 
medicine,  but  as  the  greatest  medical  character  of  all  times.  In  founding 
a  school  of  medicine,  he  took  the  final  step  which  made  his  influence 
permanent.  The  School  of  Cos  embodied  his  teachings  and  ideals. 
Through  it,  his  medicine  and  his  inspiration  were  handed  on,  not  only 
to  his  pupils,  but  to  succeeding  generations.  Such  was  his  influence  that 
his  teachings  held  sway  almost  unchallenged  for  two  thousand  years, 
while  some  of  his  principles  guide  us  even  today. 

Greek  Medicine  Subsequent  to  Hippocrates 

The  School  of  Cos  became  the  center  of  Hippocratic  medicine  as  the 
School  of  Cnidus  under  Euryphon  insisted  more  on  accuracy  of  diagnosis 
and  on  vigorous  treatment;  but  lacking  instruments  of  precision  and 
correct  fundamental  conceptions  of  disease,  vigorous  treatment  was 
applied  frequently  to  the  patient's  serious  detriment  and  ofttimes  with 
disastrous  results. 

The  interest  taken  in  medicine  just  subsequent  to  Hippocrates  was 
little  short  of  remarkable.  The  up-to-date  monarch  of  the  day  delighted 
in  medical  discussion  and  in  medical  problems.  Mithridates  at  Pontus 
became  the  most  famous  of  toxicologists.  Attains  of  Pergamus 
planted  a  famous  poison  garden,  while  the  Greek  kings  of  Egypt 
exhibited  unusual  interest  in  all  things  medical.  About  300  b.c.  Ptolemy 
the  First  established  a  museum  in  Alexandria,  and  that  city  from  that 
time  on  became  the  center  of  medicine  and  of  learning  generally,  a  fact 
well  attested  by  the  fame  of  its  library.  Three  great  schools  of  medicine 
arose  subsequent  to  Hippocrates. 

( r )  The  Dogmatic  School. — It  advocated  rational  medicine,  the  cause 
being  the  important  factor  to  determine  and  remove.  Galen  credits 
Hippocrates  with  founding  this  school;  others,  Thessalus  and  Draco, 
supposedly  sons  of  Hippocrates.  Praxagorus  of  Cos,  Diodes,  the 
Alexandrine  anatomist  Herophilus,  and  Erasistratus  were  its  leading 
spirits.  They  recognized  the  necessity  of  basing  medicine  on  physiology. 
Herophilus  (student  of  Praxagorus)  and  Erasistratus  were  the  actual 
founders  of  anatomy,  physiology  still  remaining  in  the  embryonic  stage. 
Authority  in  physiology  rested  in  (a)  "  On  the  Nature  of  Man,"  a 
treatise  written  supposedly  by  Polybius,  son-in-law  of  Hippocrates,  and 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES   819 

(b)  on  "  Timaeus,"  from  the  hand  of  Plato.  Unfortunately  Plato  was 
unsound  as  a  physiologist,  and  medicine  built  on  his  physiology  lacked 
firm  foundation  and  in  consequence  suffered  greatly. 

For  a  thousand  years  the  School  of  Alexandria  flourished.  In  it  were 
made  numerous  dissections  and  many  important  anatomical  discoveries. 
It  is  credited  with  many  vivisections  on  criminals  and  captives.  In 
anatomy,  Herophilus  and  Erasistratus  worked  side  by  side,  having  a 
community  of  interests  in  anatomy  but  differing  widely  on  the  question 
of  treatment.  The  former  followed  Hippocrates,  the  latter,  while 
operating  fearlessly,  rejected  bleeding  as  too  depleting  and  adopted 
extremely  small  dosage  in  drug  therapy.  On  the  question  of  treatment, 
they  continued  irreconcilable,  each  founding  his  own  school  of  therapy. 

The  shortcomings  of  the  dogmatists,  while  numerous,  can  be  readily 
overlooked  in  the  light  of  their  high  ideals.  They  contributed  largely 
to  the  science  of  medicine,  creating  anatomy  and  establishing  as  a  prin- 
ciple medicine  based  on  physiology.  Their  weakness  lay  in  their  excess 
of  theory. 

(2)  The  Empiric  School  arose  in  Alexandria,  splitting  off  from  the 
dogmatists  about  280  B.C.  as  the  result  largely  of  the  extravagant 
theorizing  of  the  latter.  The  founders  were  pupils  of  Herophilus, 
Philinus  and  Serapion  by  name.  They  despised  anatomy,  physiology, 
and  pathology,  were  uninterested  in  the  cause  of  disease,  claiming  that 
"  the  cure  and  not  the  cause  "  was  the  vital  question.  They  accordingly 
adopted  symptomatic  treatment,  and  with  it,  a  correspondingly  narrow 
point  of  view.  They  sought  specifics  and  increased  markedly  the  number 
of  remedies  without  improving  treatment. 

One  great  man  they  produced,  namely,  Heraclides  of  Tarentum,  born 
B.C.  230,  the  greatest  therapeutist  of  ancient  times.  He  might  qualify 
to-day  as  a  pharmacologist.  Though  an  empiricist,  he  did  much  to 
combat  the  evils  of  that  system.  He  investigated  the  clinical  effect  of 
drugs,  utilizing  only  those  he  had  personally  studied,  and  he  did  much  to 
place  therapy  on  a  scientific  basis.  His  greatest  work  was  entitled, 
"  On  the  Preparation  and  Proving  of  Drugs,"  in  which  he  points  out 
the  virtues  of  opium,  which  he  finds  useful  in  sleeplessness,  spasm  and 
colic,  cough,  cholera,  and  serpent's  bites,  and  locally  in  the  form  of 
poultices  in  painful  ophthalmia.  He  advocated  water  for  fever  and 
treated  brain  fever  on  logical  grounds.  His  principles,  had  they  been 
followed,  would  have  relegated  empiricism  to  the  background  and 
resulted  in  rational  treatment  based  on  experimental  therapy. 

Aristotle,  the  greatest  of  Greek  philosophers,  was  a  great  exponent  of 
empiricism.  As  the  originator  of  logic,  he  was  naturally  forced  to 
forsake  the  dogmatists  with  their  innumerable,  untenable  theories.     In 


820     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

fact,  so  far  as  medicine  is  concerned,  he  devoted  himself  almost  entirely 
to  criticisms  of  the  theories  of  the  dogmatists.  Constructively  he  labored 
with  anatomy,  in  which  field  he  rivaled  even  the  founders  of  the 
Alexandrine  School. 

The  famous  tripod,  the  basis  of  the  empirical  system  of  therapeutics, 
supposedly  made  possible  the  discovery  or  creation  of  specifics  for 
symptoms  or  syndromes.  It  consisted  of  ( i )  observation  and  experi- 
ments (autopsies),  (2)  contemporary  and  earlier  experience  (history), 
and  (3)  conclusions  based  on  similar  conditions  (analogy).  At  a  later 
date  was  added  "  epilogism,"  whereby  past  events  could  be  inferred 
from  present  conditions. 

(3)  The  third  school,  Methodic  School,  arose  under  Roman 
influence  and  is  described  under  that  heading,  which  follows  immediately. 

Roman  Medicine 

The  march  of  time  shifts  the  scene  from  Greece  and  Alexandria  to 
Rome,  but  Roman  medicine,  as  all  medicine  until  the  time  of  Harvey, 
was  Hellenic,  in  reality,  reflected  Greek  medicine. 

Asclepiades  was  the  first  great  physician  of  Rome,  incidentally  the 
most  successful  practitioner  of  ancient  times  and  the  prototype  of  the 
fashionable  physician.  He  introduced  into  medicine  a  theory  important 
because  it  subsequently  became  the  foundation  of  methodism,  and  at  a 
still  later  date  reappeared  in  the  form  of  Bruonianism.  According  to 
him  the  body  consists  of  various-sized  atoms  with  intervening  channels 
and  pores  through  which  the  smaller  atoms  circulate.  Disease  consists 
of  relative  changes  in  the  size  of  the  pores  and  particularly  in  the  block- 
ing of  pores.  He  also  believed  that  alterations  in  the  solids  of  the  body 
could  cause  disease  as  well  as  humeral  changes,  drew  a  clear  distinction 
between  acute  and  chronic  diseases,  and  was  a  great  advocate  of  air  as 
a  therapeutic  agent. 

The  Methodic  School. — This,  the  last  of  the  great  schools  of  antiquity, 
found  its  origin  in  the  principles  enunciated  by  Asclepiades.  Themison, 
despising  the  dogmatists  in  their  search  for  specifics  for  the  cure  of 
symptoms,  founded  a  simpler  system  of  medicine  based  on  the  fact  that 
diseases  have  symptoms  in  common.  Symptoms  are  the  result  of  the 
relaxation  or  contraction  of  pores,  for  Themison  worked  on  the  principle 
contraria  contrarins;  and  drugs  were  found,  laxatives  and  astringents,  to 
relax  the  contracted  and  constrict  the  relaxed.  These  doctrines  were 
brought  to  their  greatest  stage  of  perfection  by  Thessalus,  who  intro- 
duced alterative  treatment  and  laid  great  stress  on  the  subject  of 
diet. 

The  medicine  of  Rome  was  the  medicine  of  Galen.     It  is  true  that 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES   821 

Celsus,  the  "  Cicero  Medicorum,"  wrote  "  De  Re  Medicina,"  which  out- 
Hned  perhaps  better  than  any  other  pubhcation  the  medicine  of  his  time. 
But  Celsus  was  not  merely  a  doctor.  He  wrote  equally  well  on  many 
subjects.  He  tells  us  that  in  his  day  medicine  was  divided  into  three 
fields,  "  dietetics,  pharmaceutics,  and  chirurgics," 

Galen,  131-200,  was  also  a  founder  of  a  system — one  that  combined 
much  of  the  best  of  dogmatism  and  empiricism,  and  also  of  methodism, 
although  to  the  latter  he  was  utterly  opposed.  Physiologist  and  anato- 
mist, as  well  as  practicing  physician,  he  wrote  prolifically  on  many  sub- 
jects. Through  him  comes  to  posterity  much  of  our  knowledge  of  Greek 
medicine. 

Public  opinion  in  Rome  being  adverse  to  anything  quite  so  brutal  as 
the  dissection  of  the  human  body,  as  an  anatomist  he  dissected  various 
animals,  thereby  laying  the  foundation  for  comparative  anatomy.  He 
recognized  the  three  coats  of  arteries,  and  demonstrated  that  the  vessels 
did  not  contain  only  air.  His  physiology,  like  that  of  the  dogmatists, 
was  marred  by  much  theory.  Long  before  the  discovery  of  oxygen  he 
pondered  over  the  question  of  body  heat,  declaring  that,  when  that  part 
of  air  which  supports  combustion  was  identified,  we  would  have  the 
secret  of  life  and  of  body  temperature.  To  him  belongs  the  credit  of 
distinguishing  motor,  sensory,  and  mixed  nerves,  for  he  recognized  their 
true  role  in  the  organism. 

Galen's  medicine  rested  on  anatomy  and  physiology.  "  Disease,"  he 
says,  "  is  an  abnormal  afifection  of  the  body,  giving  rise  to  a  lesion  of 
function,  and  may  affect  an  individual  organ,  a  system,  or  the  body  as  a 
whole."  He  recognized  three  kinds  of  causes,  exciting,  predisposing, 
and  proximate.  Symptoms  are  of  three  varieties:  (i)  altered  function; 
(2)  vitiated  qualities;  and  (3)  results  of  these  two,  morbid  excretion  and 
retention.  He  differentiated  signs  and  symptoms.  Signs  to  him  might 
be  either  diagnostic  or  prognostic  in  character. 

In  his  therapy  he  accepted  experience  with  the  empiricists,  but  recog- 
nized the  cause  as  the  fir^  indication  in  treatment,  thus  upholding  the 
dogmatists  in  rational  therapy.  But  symptoms  also  served  as  indications 
and  could  be  met  sometimes  by  similars  and  at  others  by  contraries.  In 
addition,  other  considerations  were  important  in  indications,  namely, 
temperament,  season,  and  environment. 

In  the  history  of  medicine,  Galen  alone  has  vied  seriously  with 
Hippocrates.  To  be  sure,  he  had  the  advantage  of  500  years  of  progress. 
For  a  thousand  years  his  principles  and  practice,  though  somewhat  modi- 
fied by  mysticism  and  magic,  held  sway  through  the  middle  ages.  For 
leadership  he  competed  with  Hippocrates,  but  untinctured  Greek  medicine 
on  being  ushered  into  western  civilization  proved  its  superiority  with  the 


822     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

result  that  Hippocrates  was  adjudged  the  true  father  of  medicine,  even 
as  he  is  today. 

Influence  of  Christianity  on  Medicine 

With  the  advent  of  Christianity  a  mixture  of  rehgion  and  medicine 
was  again  attempted  with  the  usual  result,  lack  of  progress,  which 
lasted  in  this  instance  for  a  thousand  years.  Christianity  influenced  medi- 
cine in  three  ways:  ( i )  by  restoration  of  primitive  theories  of  disease; 
(2)  by  restriction  of  free  thought;  (3)  by  religious  controversies  which 
monopolized  the  best  efforts  of  thinkers  for  centuries. 

Arabian  Medicine 

In  the  year  632,  wild  barbarian  tribes  from  Arabia  descended  upon 
the  Roman  Empire  and  within  a  century  stripped  her  of  her  most  valued 
eastern  provinces.  Imagine  the  surprise  of  Europe  when  the  victorious 
barbarians  demanded  in  the  terms  of  peace  the  right  to  collect  and 
purchase  Greek  manuscripts.  But  the  Arabs  were  not  altogether  bar- 
barians. Wild  and  vigorous  by  nature,  they  were  nevertheless  endowed 
mentally  with  great  love  of  learning. 

The  cradle  of  Arabic  medicine  was  at  Gondisapor,  where  the  Nes- 
torian  School  was  located,  and  where  later  there  arose  one  of  the  most 
famous  hospitals  and  libraries  of  medieval  times.  These  people  were 
remarkable  as  translators  and  compilators,  and  through  their  efforts 
much  that  was  good  in  ancient  medicine  was  translated,  preserved,  and 
handed  down  to  western  civilization. 

Although  Arabian  medicine  is  replete  with  interesting  anecdotes,  no 
great  progress  was  made.  The  torch  of  Greek  medicine  was  kept  burning 
in  Arabia  while  elsewhere  it  was  stifled  or  allowed  to  go  out.  Two  only 
of  the  many  interesting  figures  of  Arabian  medicine  will  be  mentioned, 
Rhazes,  "  the  Experimentator,"  and  Avicenna,  "  the  Versatile." 

Rhazes  gave  the  first  description  of  measles  and  of  smallpox.  He 
experimented  with  drugs  both  on  animals  and  humans,  found  metallic 
mercury  markedly  toxic  for  monkeys,  and  introduced  the  extensive  use 
of  mercurial  inunctions.  His  "  Continens  "  in  nine  volumes  was  a  store- 
house of  information  for  succeeding  generations. 

Avicenna's  "  Canon,"  however,  surpassed  in  popularity  all  other 
medical  writings  of  Arabian  origin.  In  it  he  attempted  and  partially 
succeeded  in  reviving  the  teachings  of  Galen  and  Aristotle.  The  Canon 
became  the  textbook  of  medicine  for  the  following  four  centuries. 

During  the  five  hundred  years  that  Arabia  flourished,  hospitals,  scien- 
tific institutions,  academies  of  learning,  and  great  libraries  sprang  into 
existence  at  Bagdad,  Cairo,  Damascus,  Cordova,  and  Gondisapor.     The 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES   823 

first  book  exclusively  devoted  to  surgery  appeared,  the  work  of  Albucasis. 
Drug  therapy  flourished  as  never  before.  The  first  "  Pharmacopeia  " 
was  issued  from  the  hospital  at  Gondisapor.  Mesue  the  Younger  in 
1015  wrote  a  book  on  Materia  Medica.  In  these  publications  drugs  intro- 
duced or  popularized  by  Arabian  physicians  are  duly  discussed,  such  as 
camphor,  senna,  cubebs,  rhubarb,  cloves,  musk,  syrups,  rose  water,  and 
alcohol.  These  works  served  as  the  basis  for  the  western  pharmacopeias 
and  were  consulted  almost  to  our  own  times. 

During  the  dark  ages,  medicine  degenerated  into  medieval  scholas- 
ticism. The  School  of  Salerno  rose  and  fell  (1000-1200).  The  thir- 
teenth century  appears  brilliant  mainly  because  of  its  somber  background. 
Medicine  produced  but  one  outstanding  figure  prior  to  Basil  Valentine 
and  Paracelsus,  namely,  Arnold  di  Villanova,  1235-1312,  one  of  the  early 
members  of  the  faculty  of  the  famous  School  of  Montpellier.  Like  other 
great  men  of  early  times,  he  also  was  versatile,  in  fact,  a  doctor  in  four 
faculties,  medicine,  law,  theology,  and  philosophy.  His  chief  claim  to 
our  attention,  however,  is  by  virtue  of  his  interest  in  alchemy,  and  his 
search  for  the  universal  remedy,  or  the  "elixir  of  life."  Alcohol,  to 
his  mind,  constituted  the  nearest  approach.  With  it  he  made  extracts  of 
various  plants,  laying  in  this  way  the  foundation  for  our  present  tinctures. 

Medicine  of  the  Renaissance 

With  the  revival  of  learning  came  the  revival  of  medicine.  At  this 
time  the  mystics  or  astrologers  were  in  the  ascendency,  and  the  adminis- 
tration of  medicine  was  controlled  largely  by  the  signs  of  the  Zodiac. 
Witches  were  being  industriously  hunted  down.  Alchemy  was  beginning 
to  play  a  role  in  the  life  of  the  people,  especially  since  alchemists  were 
devoting  their  attention  to  medicinal  remedies  instead  of  transmutation 
of  metals.    In  this  setting  appeared  Basil  Valentine  and  Paracelsus. 

Basil  Valentine,  the  Benedictine  monk  of.  Erfurt,  is  shrouded  in 
mystery.  His  works  were  not  published  until  a  century  after  his  death, 
and  by  some  are  considered  to  be  from  the  hand  of  Paracelsus.  On  the 
contrary,  others  hold  that  Valentine  actually  supplied  the  ideas  so 
loudly  acclaimed  by  and  usually  accredited  to  Paracelsus.  Valentine's 
labors  in  alchemy  resulted  in  the  recognition  of  salts  of  antimony, 
nitrates  of  mercury,  zinc,  bismuth,  hydrochloric  acid,  sugar  of  lead,  and 
in  methods  of  producing  sulphuric  acid  and  ammonia.  To  mercury  he 
ascribes  great  value,  but  "  the  noblest  of  drugs  is  the  quintessence  of 
antimony." 

Paracelsus,  1 493-1 541,  justly  or  unjustly,  receives  the  credit  of  being 
the  founder  of  medical  chemistry.  He  has  been  called  the  Luther  of 
Medicine.     Bombastic,  conceited,  abusive,  and  scurrilous  in  his  attacks 


824     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

on  his  predecessors  and  contemporaries,  he  is  difficult  to  appraise.  To 
some  he  is  a  second  Hippocrates,  to  others  a  mere  blatant  mountebank. 
But  to  Paracelsus  or  Valentine,  one  or  both,  medicine  is  indebted  for  its 
start  along  chemical  lines. 

The  four  pillars  of  medicine,  according  to  Paracelsus,  were  philoso- 
phy, anatomy,  alchemy,  and  virtue.  From  the  noxious  and  indigestible 
the  stomach  separates  the  nutritious  and  digestible  and  utilizes  it.  The 
physician  must  emulate  the  stomach.  Until  he  can  find  that  which  is 
chemically  desirable,  his  medicine  will  be  a  failure.  He  believed  that  a 
specific  remedy,  "  arcanum,"  existed  for  every  disease.  Simplicity  in 
prescribing  drugs  was  the  natural  result.  He  abused  the  profession 
shamelessly  for  their  absurd  mixtures  and  concoctions,  for  he  also 
believed  in  the  quintessence  of  drugs,  possibly  a  foreshadowing  of  active 
principles  and  alkaloids. 

To  Paracelsus  the  world  was  a  macrocosm,  all  parts  of  which  are 
represented  in  man,  the  microcosm,  the  most  important  constituents 
being  sulphur,  mercury,  and  salt.  Disease  was  chemical  in  origin.  Thus, 
if  the  archeus  of  the  stomach  fails  to  separate  the  toxic  from  the  nutri- 
tive, or  the  excretory  organs  retain  them,  we  have  the  deposit  of  tartar 
on  teeth,  in  joints,  or  as  calculi  in  various  other  organs.  Tartaric  dis- 
eases of  Paracelsus  were  apparently  the  forerunners  of  "  lithemic 
diatheses." 

Antimony  he  introduced  into  medicine.  Tartar  emetic  was  his 
favorite  prescription.  So  strongly  did  he  champion  it,  and  so  bitter  was 
the  opposition,  that  at  one  time  the  University  of  Paris  demanded  from 
its  candidates  for  the  doctor's  degree  a  pledge  never  to  prescribe  it. 

It  must  be  admitted  that  Paracelsus  was  strong  in  his  belief  in  the 
supernatural,  in  magnetism,  in  astral  influences,  and  in  every  other  form 
of  humbuggery  known  to  mankind.  Similars,  sympathetic  ointment,  and 
signatures  permanently  remove  him  from  leaders  such  as  Hippocrates, 
Galen,  and  Harvey.  Nevertheless  he  called  attention  to  the  importance 
of  chemistry  as  the  foundation  for  medical  chemistry  which,  however, 
disproved  most  of  the  beliefs  which  he  so  loudly  proclaimed. 

Van  Helmont,  greatly  imbued  at  first  with  the  teachings  of  Para- 
celsus, studied  alchemy  in  relation  to  medicine,  with  the  result  that  he 
discovered  COo,  and  proof  of  the  existence  of  an  acid  in  gastric  digestion. 
Through  refutation  of  many  of  the  fantasies  of  Paracelsus,  he  did  much 
to  put  medical  chemistry  and  therapy  on  a  sounder  basis. 

The  Beginnings  of  Scientific  Medicine 

With  Harvey  commenced  experimental  medicine.  Demonstration 
and  proof  were  subsequently  demanded,  words,  customs,  authority,  and 


HISTORICAL  EVOLUTION  OF  MEDICAL  DOCTRINES   825 

theories  failing  longer  to  satisfy  the  profession.  The  "  Anatomical 
Exercise  on  the  Motion  of  the  Heart  and  Blood  in  Animals,"  1628, 
ushers  in  a  new  physiology  and  the  science  of  medicine.  Admittedly, 
the  profession  was  loathe  to  accept,  but  Harvey  defended  his  thesis 
despite  the  most  bitter  persecution,  and  in  so  doing  demonstrated  once 
and  for  all  the  advantages  of  the  experimental  method.  The  discoveries 
by  Pecquet  of  the  thoracic  duct,  by  Rudbeck  of  the  lymphatics,  the  ocular 
proof  of  the  circulation  in  the  lung  of  the  tortoise  by  Malpighi,  and  the 
introduction  of  the  microscope  by  Leeuwenhoek  still  further  established 
the  practice  of  furnishing  experimental  proof  with  any  new  claim. 

But  probably  medicine  profited  more  from  without  than  from  within. 
Not  alone  were  needed  experiment  and  demonstration  but  training  in 
methods  of  thought.  This  was  supplied  by  Bacon  and  Descartes,  the 
former  formulating  "  The  Principles  of  Inductive  Science,"  and  the 
latter  clearly  distinguishing  the  materialistic  from  the  vitalistic.  Galileo 
was  creating  the  sciences  of  physics  and  mathematics  while  Sanatorius 
through  his  assistance  was  applying  the  thermometer  and  the  scales  to 
physiology.  Borelli  was  utilizing  mechanics  and  physics  in  investiga- 
tions of  the  mechanics  of  motion.  In  other  words,  science  and  the  instru- 
ments of  science  were  coming  into  general  use  in  medicine  as  elsewhere, 
latro  chemistry,  iatro  mathematics,  and  iatro  physics  were  laying  the 
foundation  of  the  new  medicine,  and  men  were  beginning  to  specialize 
in  various  fields  of  medicine  and  its  underlying  sciences. 

Space  does  not  admit  of  detailed  consideration  of  its  various  branches, 
but  an  attempt  will  be  made  to  indicate  the  lines  along  which  the  most 
important  of  these  advanced,  while  more  detailed  consideration  will  be 
accorded  the  development  of  pharmacology  in  another  section  of  this 
article. 

The  Development  of  Clinical  Medicine 

Through  adopting  the  outstanding  features  of  Hippocrates,  the  father 
of  medicine,  Sydenham,  1624- 1689,  became  the  father  of  modern  clinical 
medicine.  Observation  and  careful  clinical  records  separated  him  from 
his  fellow  practitioners,  and  resulted  in  the  dififerentiation  by  him  of 
diseases,  and  the  discovery  of  new  diseases,  scarlet  fever  and  chorea. 
In  therapy  he  was  an  empiricist,  but  used  great  intelligence.  Progress 
may  be  made  in  three  ways:  (i)  careful  histories  of  disease,  with 
according  to  him  attempts  at  differentiation  of  essentials  from  the  non- 
essential features;  (2)  fixed  treatment  founded  on  experience;  (3) 
searching  out  specifics  in  treatment. 

He  gave  a  practical  tendency  to  clinical  medicine  which  has  been 
retained  to  our  day.    His  teachings  pervaded  the  whole  realm  of  clinical 


826     THE  PHARMACOLOGICAL  BASIS  OF  ^lEDICINE 

medicine,  and  were  accepted  and  followed  by  Baglivi  in  Italy  and  Boer- 
haave  in  Leyden.  The  former,  applying  Sydenham's  methods  of  observa- 
tion, differentiated  fevers  and  described  enteric  fever  which  was  preva- 
lent in  Rome,  and  enlarged  on  the  part  played  by  tissues  in  disease.  He 
clearly  outlined  the  clinical  effects  of  coffee,  tea,  and  chocolate,  and  as 
a  result  introduced  coffee  as  a  cure  for  headache  originating  from 
fatigue.  Boerhaave,  though  contributing  nothing  new,  inculcated  these 
principles  in  the  work  of  his  students,  and  became  the  greatest  clinical 
teacher  of  his  day. 

In  1 76 1  Leopold  Auenbrugger,  a  young  Austrian  physician,  pub- 
lished a  paper,  "  A  New  Invention  for  Discovering  Obscure  Thoracic 
Diseases  by  Percussion  of  the  Chest."  Keen  of  observation,  he  utilized 
inspection  (noting  lack  of  mobility),  palpation  and  percussion,  and 
made  many  fundamental  contributions  to  methods  of  physical  diagnosis. 
His  work,  however,  attracted  little  attention  until  unearthed  and  rein- 
troduced by  Corvissart  in  1808.  Four  years  later,  18 12,  Laennec  intro- 
duced the  stethoscope,  which  tremendously  increased  the  value  of 
auscultation.  Thereafter  clinical  medicine  was  fully  equipped  with 
methods  of  physical  diagnosis. 

Bruonianism. — A  new  system  of  medicine  was  introduced  in  1780  by 
Brown,  which  was  subsequently  known  as  Bruonianism.  According  to 
him  Life  is  a  state  produced  by  excitability  which  is  constantly  being  used 
and  constantly  replaced.  As  in  a  furnace,  fire  is  life,  coal  is  excitability, 
the  draft  is  the  stimulus.  Diseases  result  from  too  much  or  too  little 
excitability  and  stimulus,  and  are  sthenic  or  asthenic  accordingly.  Treat- 
ment consists  of  restoring  the  normal  state  of  excitability  by  regulating 
the  stimulus.  Drugs  are  stimuli  and  effectively  regulate  excitability  in 
the  following  order:  opium,  camphor,  ammonia,  musk,  alcohol,  all  of 
which  are  used  in  asthenic  states.  On  the  other  hand,  bleeding,  purga- 
tion, cold,  low  diet,  and  passive  exercise  are  debilitating  and  should  be 
used  in  sthenic  states.  Brown's  treatment  was  extremely  radical,  re- 
sulted in  great  injury,  and  would  have  brought  medicine  into  general 
disrepute  had  it  been  more  generally  adopted. 

Specialism. — At  this  period  physicians  began  to  specialize  in  internal 
medicine.*  Prominent  among  them  were  Thomas  Willis,  Sir  John 
Pringle,  John  Howard,  Wm.  Heberden,  John  Fothergill,  James  Parkin- 
son, Richard  Bright,  and  Edward  Jenner  of  vaccination  fame.  The 
names  of  Parkinson  and  Bright  were  attached  to  diseases  they  described. 
In  this  development  should  be  mentioned  the  great  John  Hunter,  who, 

*  According  to  Garrison,  specialism  existed  among  the  ancient  Babylonians,  there 
being  a  phj-sician  for  each  disease,  so  that  this  movement  must  be  looked  upon  as  the 
revival  of  specialism. 


PRESENT-DAY  FORMS  OF  THERAPY  827 

though  a  surgeon,  did  much  for  (Hagnosis.  His  interest  in  syphilis,  how- 
ever, was  unfortunate.  His  personal  auto-inoculation  experiment,  though 
based  on  the  sound  principle  of  experimentation,  was  premature  and 
retarded  progress  for  many  decades  so  far  as  syphilis  was  concerned. 

Modern  cellular  vitalism  was  the  gift  of  Rudolph  Virchow.  "  It 
breaks  up  the  old  indivisible  '  vital  force  '  distributed  throughout  the 
whole  body  or  located  in  a  few  organs  into  an  infinite  number  of 
individual  associated  vital  forces  working  together  yet  separately  and 
assigns  to  them  the  elementary  parts  (which  latter  are  considered  to  be 
cells)  in  definite  microscopic  seal."  "  Social  arrangement  or  organiza- 
tion is  beautifully  conceived,  each  part  playing  its  own  role,  influenced  by 
others,  but  performing  its  own  function  which  in  turn  affects  those  of 
other  parts." 

In  the  final  analysis,  it  is  seen  that  the  fundamental  reasons  for  the 
lack  of  progress  in  medical  treatment  were:  (i)  the  inadequate  state  of 
science,  which  made  it  impossible  to  cope  with  the  complex  problems  of 
the  human  organism,  of  disease,  and  of  the  processes  of  life;  and  (2) 
the  incorrect  methods  which  were  employed  for  approaching  the  subject, 
theories  and  speculations  predominating  rather  than  observation  and 
experimentation.  Our  forefathers  erred  in  accepting  supernatural 
agencies  as  the  basis  of  disease,  in  employing  remedies  about  which  they 
knew  but  little  for  diseases  about  which  they  knew  less,  and  in  not  having 
true  conceptions  of  either  physiological  or  pathological  processes.  Their 
fallacies  resulted  from  dealing  with  ideas  instead  of  facts. 

The  introduction  of  the  "  experimental  method  "  opened  up  new- 
channels  in  medicine  through  which  science  has  flowed  in  ever  increasing 
volume.  The  development  of  these  so-called  underlying  sciences  has 
made  possible  scientific  medicine. 


Present-day  Forms  of  Therapy 

Rational  Therapy 

Rational  therapy  is  a  consummation  devoutly  to  be  wished — true 
rational  therapy — treatment  based  on  science  and  fact.  It  includes  all 
the  elements  necessary  to  success  in  the  treatment  of  the  individual  case 
and  for  the  progress  of  medicine  at  large.  It  necessitates  a  correct 
diagnosis,  a  grasp  of  physiologic  pathology,  legitimate  indications,  for 
treatment,  and  the  correction  of  deranged  functions  along  rational  lines. 
The  indications  for  rational  treatment  are  derived  from  three  sources : 

(a)    Etiology. — Removal  of  the  cause  constitutes  radical  treatment 


828     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

and  effects  cures  in  conditions  in  which  irreparable  damage  has  not 
already  resulted.  This  is  specific  therapy,  the  ultimate  towards  which 
all  treatment  strives.  Unfortunately  its  application  is  restricted  owing 
to  existing  limitations  in  the  science  of  medicine.  All  too  frequently  the 
cause  is  unknown,  the  mechanism  and  development  of  clinical  manifesta- 
tions obscure,  conditions  usually  precluding  specific  therapy.  Neverthe- 
less in  this  field,  treatment  has  made  great  progress  during  the  last  decade. 
Specific  therapy  includes  representatives  of  drug,  serum,  vaccine,  and 
organotherapy,  the  group  of  diseases  subject  to  direct  control  being  con- 
stantly on  the  increase.  Thus  we  have  quinine  in  malaria,  mercury  and 
arsenic  in  syphilis,  arsenic  and  antimony  in  trypanosomiasis,  specific  sera 
for  many  infectious  diseases,  desiccated  thyroid  in  myxedema,  and 
pituitary  extract  in  diabetes  insipidus.  The  chemical  nature  of  some 
of  the  hormones  has  been  determined,  a  few  have  been  isolated,  and 
in  one  instance,  namely,  thyroxin  (the  active  principle  of  the  thyroid), 
it  has  been  actually  synthesized  and  demonstrated  to  have  all  the  effects 
of  the  desiccated  gland.  With  thyroxin  metabolism  can  be  profoundly 
affected.  Thus  it  is  seen  that  specific  therapy  leads  to  fundamentals 
and  will  in  all  probability  constitute  the  basis  of  the  scientific  treatment 
of  the  future. 

(b)  Pathology. — This  is  used  in  its  broadest  sense  and  includes  func- 
tional and  chemical  as  well  as  anatomical  changes.  Certain  pathological 
conditions  are  encountered  clinically  which  demand  a  definite  line  of 
treatment  irrespective  of  the  underlying  causes.  To  be  sure,  the  cause 
may  need  treatment  in  addition.  Thus,  outspoken  myocardial  insuf- 
ficiency calls  for  treatment,  per  se,  independently  of  whether  it  is  due 
to  myocarditis,  secondary  to  syphilis,  rheumatism,  arteriosclerosis, 
nephritis,  focal  infection,  exophthalmic  goiter,  or  to  some  valvular  lesion. 
The  underlying  cause  may  also  demand  its  own  treatment  simultaneously 
or  at  some  subsequent  time.  Similarly  uremia  calls  for  a  certain  line  of 
treatment  irrespective  of  whether  it  is  due  to  nephritis,  polycystic  kidneys, 
or  obstruction  of  the  lower  urinary  tract;  and  marked  acidosis  demands 
its  own  therapy  independently  of  the  underlying  diabetes  or  nephritis. 

(c)  Symptoms. — Generally  speaking,  symptomatic  treatment  should 
be  avoided  except  as  a  last  resort  when  other  methods  fail.  Symptoms 
are  the  expressions  of  deranged  function  and  often  blessings  in  disguise. 
Their  nature  and  cause  should  be  determined.  Treatment  should  first  be 
directed  not  to  them  but  to  their  cause  and  to  the  correction  of  the 
deranged  function.  This  failing,  and  particularly  where  the  symptoms 
occasion  great  distress  or  endanger  vital  functions  or  life  itself,  general 
measures  for  symptomatic  relief  may  be  adopted;  but  the  clinical  investi- 
gation should  continue  and  due  caution  be  exercised  that  no  harm  is  done. 


PRESENT-DAY  FORMS  OF  THERAPY  829 

Symptomatic  treatment  is  often  the  easiest  for  the  doctor,  but 
injudiciously  applied,  is  responsible  for  most  of  the  mistakes  and  many 
of  the  tragedies  of  practice. 

Empirical  Therapy 

This  is  based  on  clinical  experience,  previous  results  serving  as  the 
guide,  the  cause  and  mechanism  involved  and  the  reason  for  cure  remain- 
ing obscure.  The  term  "  purely  empirical  "  carries  with  it  a  certain 
element  of  reproach.  The  name  has  become  a  term  of  opprobrium. 
While  it  is  not  the  intent  of  the  author  to  champion  empiricism,  it 
should  be  remembered  that  "  experience  is  a  good  teacher,"  and  that 
the  empirical  treatment  of  one  period  has  occasionally  become  the  rational 
or  specific  therapy  of  a  later  date.  In  a  considerable  number  of  instances 
clinical  experience  has  furnished  irrefutable  evidence  of  the  efficacy  of 
the  therapeutic  measure  long  before  the  underlying  cause  and  the  char- 
acter of  the  disease  have  been  determined.  For  instance,  mercury  was 
used  in  syphilis,  and  quinine  in  malaria  before  the  tryponema  and  the 
Plasmodium  were  discovered,  while  digitalis  was  used  in  the  treatment 
of  dropsy  before  the  express  relationship  of  dropsy  to  myocardial  insuf- 
ficiency was  recognized.  In  these  and  many  other  instances  therapy  has 
outdistanced  the  other  branches  of  medical  science,  a  matter  of  com- 
mendation and  not  of  reproach  so  far  as  treatment  is  concerned. 

Empiricism  in  therapy  is  permissible  at  times,  but  only  if  the  proof 
of  its  efficacy  is  convincing.  Inability  to  explain  is  admission  of  igno- 
rance. Empirical  treatment  may  constitute  the  starting-point  of  clinical 
investigation,  but  invariably  demands  controls,  accurate  observation  of 
results  efifected,  critical  judgment,  and  simultaneously  intensive  search 
for  the  causal  factors  concerned.  Such  scrutiny  ofttimes  reveals  ineffec- 
tiveness, whereupon  the  treatment  must  be  abandoned. 

Supernatural  Therapy 

This  is  based  on  the  primitive  conception  of  disease,  and  is  perhaps 
the  oldest  of  all  forms  of  therapy.  It  is  primitive,  fundamental,  and 
fixed.  The  credulity  of  the  heathen  amuses  us;  in  fact,  in  our  wisdom 
we  smile.  Wherein  does  our  own  childhood  teaching  differ?  It  gives 
us  faith  and  casts  a  cloak  over  reason.  Just  as  our  Greek  forefathers 
slept  before  the  temples  of  Esculapius,  so  we  make  pilgrimages  to  Rome 
or  visits  to  the  shrine  of  St.  Anne  de  Beaupre.  Absent  treatment  today 
is  as  effective  as  was  the  sympathetic  ointment  of  Paracelsus.  Mental 
treatment,  suggestion,  and  faith  healing  are  unquestionably  helpful  at 


830     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

times,  but  their  use  should  be  supplemented  by  all  that  science  and  sound 
experience  can  furnish. 

Baseless  Therapy 

This  is  the  "  therapy  of  fancy "  of  Lauder  Brunton.  Although 
medical  science  has  caused  the  "  old  vessels  which  once  held  human 
beliefs  "  to  be  abandoned,  therapy  based  on  these  beliefs  still  persists. 
Often  lack  of  time  or  ignorance  prevents  the  busy  practitioner  from 
applying  the  four  fundamentals  of  treatment.  Only  too  frequently  the 
outstanding  symptom  is  treated,  headache  instead  of  uremia,  or  loss  of 
weight  instead  of  diabetes. 

At  times  polypharmacy  replaces  pathology,  undiagnosed  conditions 
being  met  by  mixtures  of  drugs,  the  action  of  any  one  of  which  is  but 
poorly  understood.  Fortunately  the  inclusion  in  the  curriculum  of 
medical  schools  pharmacology  is  rapidly  doing  away  with  this  practice. 
Perhaps  more  than  any  other  factor,  the  large  pharmaceutical  firms  are 
responsible  for  the  remnants  of  polypharmacy  which  still  persist. 

Incredible  as  it  may  seem,  the  therapy  of  many  well-trained  physicians 
is  directed  not  by  their  knowledge  of  the  action  of  drugs,  but  by  the 
greed-inspired  claims  of  pharmaceutical  houses.  Pamphlets  dealing  with 
theoretical  and  scientific  considerations  somewhat  beyond  the  training  of 
the  average  physician  and  outlining  new  discoveries  of  merit  arc  placed 
in  the  hands  of  the  practitioner  for  his  seduction.  Because  the  informa- 
tion is  new  and  smacks  of  science,  and  because  he  fails  to  recognize 
fallacies  in  supposed  correlations  presented,  he  is  led  into  grievous  error; 
to  wit,  the  application  of  baseless  therapy  in  the  belief  that  he  is  treating 
his  patient  along  approved  modern  scientific  lines. 

Textbooks  of  therapeutics  are  the  basis  of  much  baseless  therapy. 
Authority,  that  which  dominated  medicine  from  Hippocrates  to  Hunter, 
is  still  effective.  The  conscience  of  the  physician  is  clear  despite  the 
disastrous  outcome  provided  authority  exists ;  i.e.  the  finger  can  be 
pointed  to  the  printed  page.  Fortunately  the  day  of  prescribing  the 
name  of  a  drug  for  the  name  of  a  disease  is  passing  with  the  advent 
of  modern  works  on  pharmacology. 

Diagnostic  Therapy 

So  certain  and  so  well  understood  are  the  actions  of  certain  drugs, 
that  they  are  used  at  times  to  assist  in  arriving  at  a  diagnosis.  Thus  it  is 
possible  to  determine  factors  important  in  diagnosis :  ( i )  Whether  or  not 
a  certain  mechanism  is  hyper-  or  hypo-active  by  observing  the  effect  upon 
it  of  standard  stimuli.  "  Believing  that  excessive  reaction  to  pilo- 
carpin  on  the  one  hand,  or  to  epiniphrin  (adrenalin)  on  the  other,  points 


FACTORS  OF  PROGRESS  IN  THERAPY  831 

to  a  high  tonus  (or  a  high  excitability)  of  the  autonomic  nervous  system 
in  one  instance,  and  of  the  sympathetic  nervous  system  in  the  second, 
Eppinger  and  Hess  (")  have  made  use  of  injections  of  these  two  sub- 
stances for  diagnostic  purposes.  (2)  Whether  or  not  a  function  is  dis- 
turbed or  a  lesion  exists,  by  giving  drugs  which  accentuate  or  minimize 
the  underlying  defects  thereby  accentuating  or  removing  the  symptoms 
and  signs.  In  this  connection  (a)  atropin  and  digitalis  are  utilized 
in  relation  to  questions  of  conductivity  and  heart  block,  atropin  removing 
partial  block,  and  digitalis  increasing  it.  (b)  Nitrites  are  used  in  ques- 
tionable cases  of  mitral  stenosis.  (3)  Whether  or  not  cure  or  specific 
reactions  result  from  the  use  of  specific  remedies.  Thus  in  districts 
where  malaria  is  prevalent,  fevers  quickly  subsiding  on  the  administra- 
tion of  quinine  are  frequently  accepted  as  malarial,  or  vice  versa. 
Therapeutic  tests  are  resorted  to  frequently  where  the  existence  of 
syphilis  is  in  question. 

By  such  means  diagnoses  can  be  deduced  at  times.  Thus  through 
knowing  the  seat  of  action  it  is  possible  to  determine  the  functional  state 
of  the  mechanism  involved,  to  bring  out  greater  defects,  or  to  remove 
an  etiological  factor  through  the  use  of  etiotropic  remedies. 

Prophylactic  Therapy 

The  miracles  wrought  by  preventive  medicine  in  the  prevention 
of  typhoid  fever,  smallpox,  etc.,  are  made  possible  through  immunity 
reactions,  and  do  not  at  the  present  time  come  in  the  province  of 
pharmacology. 

On  the  other  hand,  specific  drug  therapy  has  already  achieved  great 
results  in  relation  to  protozoal  diseases  and  to  local  bacterial  infections, 
especially  the  venereal  diseases.  Thus,  quinine  is  effective  against 
malaria,  salvarsan  against  syphilis,  while  mercury  ointment  prevents  the 
development  of  s)philis  and  injections  of  protargol  or  argyrol,  the 
development  of  gonorrhea. 

Factors  Responsible  for  Progress  in  Therapy 

Having  considered  the  factors  which  retarded  the  progress  of 
therapy,  let  us  attempt  to  identify  and  analyze  the  factors  responsible 
for  the  remarkable  progress  of  recent  years.  Innumerable  influences  have 
borne  on  the  problem,  but  the  more  important  can  be  selected  and 
analyzed.  Some  of  them  are  too  broad  to  be  dealt  with  other  than  in  a 
general  way,  while  some  which  apply  directly  to  pharmacology  will  be 
considered  in  more  detail.    These  factors  mav  be  enumerated  as  follows : 


832     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

(i)  The  most  important  factor  perhaps  is  the  advancement  of 
science  generally.  Without  science  and  its  methods,  medicine  would  have 
remained  an  art. 

(2)  The  development  of  pharmacology  whereby  remedies,  whose 
actions  are  understood,  are  directed  to  the  correction  of  derangements  in 
physiological  functions. 

(3)  The  chemical  basis  of  pharmacology;  the  recognition  of  the 
relationship  of  pharmacological  action  to  chemical  constitution  of  drugs 
and  the  development  of  remedies  on  this  basis. 

(4)  The  development  of  specific  chemotherapy  and  experimental 
therapeutics  whereby  remedies  are  scientifically  developed  and  directed 
towards  the  removal  of  specific  causes  of  disease. 

(5)  The  discovery  of  microorganisms  and  their  relation  to  disease. 
This  is  directly  responsible  for  the  development  of  bacteriology  and 
immunology  and  for  the  development  of  preventive  medicine,  the  most 
important  advance  in  medicine  of  all  times.  It  has  also  revolutionized 
surgical  practice,  bringing  all  structures  within  the  province  of  the 
operator  through  the  application  of  aseptic  and  antiseptic  principles. 

(6)  Recognition  of  the  role  played  in  the  organism  by  glands  of 
internal  secretion,  their  relationship  to  metabolism  and  growth  in  health 
and  disease,  and  the  development  of  endocrinology  and  organotherapy. 

(7)  The  adoption  of  a  functional  conception  of  disease  with  the 
consequent  direction  of  treatment  toward  restoration  of  function. 

(8)  Organization  of  medical  efifort  (schools,  hospitals,  medical 
institutions,  and  societies)  and  adequate  channels  of  communication. 

An  attempt  will  be  made  to  outline  the  more  important  advances  along 
these  lines,  and  the  effects  of  each  of  these  factors  upon  medicinal  doc- 
trines and  practice.  Obviously  it  is  impossible  to  do  more  than  select 
outstanding  examples  in  each  field.  These  will  be  dealt  with  in  some 
detail,  however,  in  order  to  reveal  the  development  of  principles. 

(i)  Advancement  of  Science  and  Progress  of  Medicine 

Progress  has  come  through  the  advancement  of  science.  The  Greek 
mind  was  active,  inquisitive,  and  speculative,  the  age  dark  scientifically 
though  brilliant  perhaps  philosophically.  The  Greeks  had  facts,  isolated 
but  not  correlated.  Experimentation  was  possible,  but  lacking  laws  of 
science  they  could  neither  appreciate  its  value  nor  did  they  possess  its 
methods. 

Let  us  visualize  the  difficulties  confronting  Hippocrates.  Let  us  sup- 
pose him  confronted  by  a  case  of  malaria.  The  patient  complains  of 
chills,  fevers,  sweats,  and  aching  in  his  bones  and  muscles.     Malaria  has 


FACTORS  OF  PROGRESS  IN  THERAPY  833 

never  been  described  and  none  of  his  colleagues  has  ever  encountered  a 
similar  case.  He  studies  the  patient  and  confirms  the  temperature  changes 
with  his  hands.  He  offers  a  purgative  or  bleeds  him  and  keeps  him  in 
bed.  The  symptoms  continue.  How  can  he  proceed  ?  Examination  of  the 
blood  is  impossible,  for  he  has  no  microscope,  and  nothing  is  known  of 
the  character  of  the  blood,  of  corpuscles,  red  or  white,  or  of  plasmodia. 
How  is  he  to  know  that  the  mosquito  has  caused  the  infection?  No  one 
has  discovered  insects  as  carriers  of  disease.  How  is  he  to  know  of 
cinchona  which  grows  in  far-off  Peru?  Quinine  has  not  yet  been 
isolated.  Can  he  transfer  the  disease  to  animals  ?  Syringes  have  not  yet 
come  into  existence,  experimental  production  of  disease  has  never  been 
attempted,  and  the  maltreatment  of  an  animal  might  cost  him  his  life. 
Pathology  is  unknown  and  if  in  the  event  of  death  of  his  patient  he 
obtains  an  autopsy,  he  has  no  normal  control.  What,  then,  must  he  do 
to  get  at  the  whole  truth? 

It  would  be  necessary  to:  (i)  invent  the  microscope;  (2)  invent 
methods  of  studying  blood  slides,  and  establish  the  normal  blood  picture 
with  w'hich  to  compare  the  findings  of  his  patient;  (3)  discover  the 
Plasmodium  of  malaria;  (4)  recognize  mosquitoes  as  hosts  and  deter- 
mine their  role  as  hosts;  (5)  prove  the  possibility  of  transmission  from 
mosquito  to  man  and  work  out  the  life  cycle  of  the  plasmodium;  (6) 
select  cinchona  from  the  thousands  upon  thousands  of  plants,  and  in 
this  particular  instance  it  would  have  involved  the  discovery  of  the  new 
world;  (7)  isolate  quinine,  for  which  procedure  must  be  developed  the 
science  of  chemistry;  (8)  create  protozoology  and  experimental 
pathology.  Since  it  has  taken  the  best  efforts  of  science  and  medicine 
twenty-five  centuries  to  accomplish  these  things,  we  can  scarcely  hold 
Hippocrates  responsible  for  failing  to  handle  the  case  scientifically. 

Medicine  is  science  and  can  only  grow  with  science  generally.  Hippoc- 
rates vv'as  honest.  Recognizing  existing  limitations,  he  preferred  not  to 
go  too  deeply  into  the  question  of  diagnosis  but  to  treat  the  individual  if 
not  the  disease;  to  assist  the  "  vis  medicatrix  naturae."  We  fail  to  recog- 
nize that  the  average  citizen  of  today  has  a  larger  opportunity  of  casually 
acquiring  medical  science  than  was  possible  to  Hippocrates  through  a  long 
life  of  arduous  labor. 

Lauder  Brunton  (''),  writing  in  1880,  says,  "Unfortunately  we  do 
not  know  medicine  as  we  do  chemistry  and  physics.  We  have  medical 
sciences,  for  physiology,  pathology,  and  pharmacology  are  justly  begin- 
ning to  lay  claims  to  the  title ;  but  medicine  itself,  the  recognition  and 
cure  of  disease,  is  still  an  art  and  not  a  science,"  and  as  proof  thereof 
he  instances  the  same  disease,  malaria.  "We  know  that  if  a  man  pass 
through  certain  districts,  and  more  especially  if  he  sleep  in  them,  he  is 


834      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

likely  to  be  attacked  with  a  fit  of  shivering  which  often  lasting  some 
time  will  be  succeeded  by  a  burning  fever,  and  then  by  profuse  sweating, 
after  which  he  will  feel  comparatively  well  until  the  next  day,  when 
another  shivering  fit  will  come  on  at  the  same  hour,  and  run  the  same 
course  as  the  first.  We  know  that,  by  warning  the  man  against  the 
dangerous  locality,  or  by  making  him  adopt  certain  precaution,  take 
cinchona  alkaloids,  if  he  cannot  avoid  the  place,  we  may  be  able  to  prevent 
the  disease;  by  administering  one  large  dose  of  quinine  before  the 
paroxysm,  we  may  stop  its  approach,  and  by  continuing  the  remedy  we 
may  prevent  its  recurrence  altogether.  But  we  are  ignorant  of  the  nature 
of  malaria  as  we  trace  the  course  of  these  paroxysms  whatever  it  may  be. 
We  do  not  know  how  it  acts  upon  the  bodily  mechanism  so  as  to  cause 
them.  We  have  no  notion  of  the  manner  in  which  quinine  counteracts 
the  malarial  effects." 

And  this  was  scarcely  forty  years  ago.  Physiology,  pathology,  and 
pharmacology  have  more  claim  to  the  title  of  science  now,  than  then. 
Medicine  itself,  the  recognition  and  cure  of  disease,  is  rapidly  becoming 
science.  The  recognition  and  treatment  of  malaria  is  science — applied 
physiology,  pathology,  and  pharmacology. 

Today  we  know  the  cause  and  the  cure  of  malaria.  Brunton,* 
together  with  thousands  of  other  physicians,  had  at  hand  the  instruments 
necessary  for  the  solution  of  the  problem  in  1880;  Hippocrates  did  not 
in  460  B.C.  Both  were  equally  honest  in  every  respect.  Each  acted  in 
accordance  with  his  light,  with  the  state  of  science  and  of  cosmic 
consciousness. 

But  have  we  reached  the  ultimate  in  our  conception  of  malaria  and  its 
cure?  What  is  fever?  What  is  a  chill?  Why  does  segmentation  of  the 
Plasmodia  result  in  fever?  What  relation  have  dehydration  and  sweating 
to  chills  and  fevers?  Is  quinine  necessary?  What  radicle  of  quinine  is 
responsible  for  the  destruction  of  the  plasmodium  and  will  it  suffice? 
Innumerable  questions  confront  us  just  as  they  did  the  Father  of  Medi- 
cine and  Lauder  Brunton.  These,  the  future  and  science  will  solve.  All 
medicine  truly  rational  is  science,  or  fast  becoming  so. 

(2)    The  Development  of  Pharmacology 

Although  drugs  come  down  from  antiquity,  the  science,  mechanism, 
and  seat  of  their  action  is  of  quite  recent  date.  Bichat,  dissatisfied  with 
the  prevailing  opinions  of  pathology  and  treatment,  devoted  his  short  life 

*  These  statements  are  not  intended  as  derogatory  to  Sir  Lauder  Brunton.  His 
name  is  mentioned  in  this  connection,  first,  because  of  his  pharmacological  writings 
from  which  an  excerpt  is  here  presented,  and  secondly,  because  he  represented  the 
highest  type  of  physician  of  his  day  and  contributed  abundantly  to  the  sciences  of 
pharmacology  and  therapeutics. 


FACTORS  OF  PROGRESS  IN  THERAPY  835 

to  the  former.  Fired  by  his  spirit,  his  pupil  Magendie  took  up  his  work 
and  did  for  treatment  what  Bichat  had  done  for  pathology,  namely,  laid 
the  cornerstone  of  an  underlying  science.  Perhaps  more  important  than 
the  results  themselves  were  the  methods  of  his  experimentation.  His 
object  was  to  determine  the  seat  of  the  action  of  a  drug.  Utilizing 
upas,  which  contains  strychnine,  he  attempted  to  prevent  it  reaching  the 
cord  and  again  applied  it  directly,  finding  in  the  first  instance  that  it  did 
not  cause  convulsions  but  that  in  the  latter  it  readily  did.  The  first 
pharmacological  experiment,  therefore,  was  the  demonstration  of  the 
action  of  strychnine  on  the  cord. 

This  appears  a  matter  of  simplicity  today,  but  was  a  new  conception 
in  Magendie's  day.  He  first  used  upas  subcutaneously,  getting  con- 
vulsions in  three  minutes.  The  prevailing  explanation  concerning 
absorption  and  action  of  upas  was  that  it  was  absorbed  from  the  wounds 
into  the  blood,  was  carried  to  the  heart  and  thence  to  all  organs  including 
the  nervous  system,  where  its  special  action  was  exerted.  It  was  in  his 
method  of  proving  this  explanation  that  Magendie  founded  pharma- 
cology. He  did  not  take  it  for  granted,  he  demonstrated  and  proved  it. 
As  these  constitute  the  first  pharmacological  experiments,  it  seems  ad- 
visable to  present  them. 

(a)  Channels  and  Rate  of  Absorption. — Injections  into  pleural  and 
peritoneal  cavities  resulted  immediately  in  the  appearance  of  symptoms, 
into  an  isolated  loop  of  intestine,  after  six  minutes,  into  a  full  stomach, 
after  one-half  hour.  Absorption  occurred  from  the  large  bowel,  bladder, 
and  vagina,  but  was  slower  as  it  was  also  from  the  stomach  isolated  by 
ligatures  at  the  cardia  and  pylorus. 

(b)  Proof  that  Poison  Acts  Through  the  Circulation. — Injection 
into  the  jugular  vein  was  much  more  quickly  followed  by  convulsions  than 
injection  into  the  femoral  arteries,  for  in  the  latter  the  peripheral  circu- 
lation must  be  made  before  the  blood  reached  the  heart  and  eventually 
the  cord.  To  rule  out  the  so-called  sympathetic  action  suggested  by  his 
contemporaries,  he  isolated  the  limb  except  for  the  blood  vessels,  injected 
the  drug,  and  obtained  the  convulsions.  This  experiment  he  repeated 
successfully  after  severing  artery  and  vein  and  connecting  their 
divided  ends  by  goose  quills.  He  thereby  ruled  out  lymphatics  and 
nerves. 

(c)  Proof  of  Seat  of  Action  in  Cord. — Injections  were  made  into 
carotid  artery,  no  convulsion  resulting  until  suflficient  time  had  elapsed 
for  the  drug  to  complete  the  circulation  and  reach  the  cord,  whereby  the 
brain  as  the  seat  of  action  was  ruled  out.  The  destruction  of  the  cord 
by  a  probe  prevented  the  appearance  of  tetanus,  dorsal  cord  destruction 
preventing  tetanus  of  forelegs,  lumbar  destruction,  tetanus  of  hind  legs. 


Bs6     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

Following  the  exposure  of  the  cord  by  operation,  direct  application  to  the 
cord  caused  immediate  tetanus.  Thus  for  the  first  time  was  revealed  not 
only  the  seat  of  action,  but  also  the  channels  of  absorption  and  trans- 
portation, and  the  mechanism  of  action. 

He  next  attempted  to  apply  his  discoveries  clinically.  Nux  vomica, 
which  was  on  the  market,  acted  much  as  upas,  and  this  he  utilized  in  a 
case  of  paralysis  with  remarkably  good  results.  He  found  later,  how- 
ever, that  it  had  already  been  used  by  M.  Fourquier,  but  its  use  was  based 
on  Magendie's  experiments. 

This  remarkable  investigation  was  followed  by  another  by  Claude 
Bernard  (*),  who  was  a  pupil  of  Magendie.  Sir  Benjamin  Brodie  (^) 
had  demonstrated  in  1812  that  curare,  an  arrow  poison  used  by  the 
Indians  in  the  valley  of  the  Amazon,  paralyzed  voluntary  muscles, 
and  that  even  after  apparent  death  the  heart  continued  to  beat  and  the 
blood  to  flow  as  evidenced  by  the  spurting  of  blood  on  section  of  an 
artery. 

Bernard  took  up  the  work  in  1844.  Three  possibilities  obtain,  an 
effect  on  the  muscle  itself,  on  the  peripheral  nerve,  on  the  central  nervous 
system.  The  effect  on  the  muscle  itself  could  be  ruled  out  by  eliciting 
response  by  a  galvanic  current  subsequent  to  curarization.  The  absence 
of  response  in  applying  the  current  to  the  nerve  located  the  seat  of  action 
in  the  nerve  or  muscle.  Was  it  nerve  trunk  or  nerve-ending?  Muscles 
and  nerve  were  soaked  in  a  curare  solution  and  it  was  found  that  on 
immersing  the  nerve  trunk  alone,  normal  reactions  followed  stimulation, 
whereas  following  immersion  of  the  muscle  no  response  could  be  elicited. 
The  seat  of  action,  therefore,  must  be  found  in  the  nerve-endings  in  the 
muscle.  Following  this,  he  demonstrated  that  the  drug  acted  locally, 
for  after  isolating  the  limb  of  a  frog  by  ligation  and  injecting  curare 
subcutaneously,  the  ligated  limb  responded  in  normal  fashion  to  stimu- 
lation despite  the  fact  that  the  rest  of  the  body  was  paralyzed. 

Little  has  been  added  to  our  knowledge  of  the  action  of  curare  since 
these  experiments  of  Bernard.  To  be  sure,  Lauder  Brunton  subsequently 
showed  the  effect  of  curare  on  the  cord  itself  and  its  slight  effect  in 
inhibiting  conduction  through  sensory  nerves.  The  neural-muscular 
junction  has  become  somewhat  better  defined  and  we  know  that  the 
nerves  and  end-organs  have  no  medullary  sheath  and  hence  are  exposed 
to  drug  action.  The  nerve-end  organs  are  complex  structures  containing 
nerve  fibrils,  which  pass  into  the  true  end-organs  or  nerve  plates,  which 
in  turn  send  branching  filaments  into  the  muscle  cells.  We  know  that 
curare  interposes  to  centrifugal  impulses  resistance  at  a  point  below  the 
nerve  fiber  and  the  actual  termination  in  the  muscle,  but  the  exact  seat  is 
still  not  known.     The  union  of  curare  with  the  nerve  is  chemical  or 


FACTORS  OF  PROGRESS  IN  THERAPY  837 

physico-chemical  in  character,  the  drug  finally  being  freed  and  excreted 
if  death  has  not  supervened.  The  curare  action  is  due  to  the  quaternary 
nitrogen  group,  a  property  held  in  common  with  tetra-methyl  and  tetra- 
ethyl  amines. 

Magendie  and  Claude  Bernard  inaugurated  a  new  epoch  in  therapy. 
Their  investigations  revealed  the  possibility  of  ascertaining  accurate 
information  concerning  the  seat  and  mechanism  of  action  of  drugs,  their 
methods  constituting  the  foundation  on  which  pharmacology  now  rests. 

Crum,  Brown  and  Eraser  O  in  1868  attacked  pharmacology  from  a 
somewhat  different  point  of  view;  namely,  the  relation  of  pharmacological 
action  to  chemical  constitution.  Their  work  elucidated  the  subject  of 
the  anchoring  of  drugs  by  cells.  It  was  they  who  first  determined  the 
chemical  character  of  curare.  They  fixed  the  responsibility  of  its  action 
on  the  quaternary  nitrogen  and  proved  that  this  action  was  held  in 
common  with  all  other  quaternary  ammonia  bases.  Their  claims  were 
subsequently  confirmed  by  Brunton  and  Cash.  Brunton  devoted  much 
time  to  pharmacology  and  scientific  therapy,  investigating  the  action  of 
an  "  ordeal  poison,"  casca,  on  the  gastrointestinal  tract,  heart,  and  circu- 
lation, and  the  action  of  digitalis  on  heart  and  circulation.  He  also 
studied  the  diuretic  action  of  digitalis.  On  pharmacological  grounds  he 
introduced  into  medical  practice  the  use  of  vasodilators. 

Schmiedeberg  exercised  a  profound  influence  on  the  development  of 
pharmacology,  to  which  he  devoted  his  long  life.  He  introduced  a  new 
method  of  pharmacological  study,  namely,  the  action  of  drugs  on  the 
frog's  heart,  which  resulted  in  a  much  clearer  conception  of  cardiac  action 
and  the  influence  on  it  of  drugs.  In  addition,  he  also  emphasized  the 
chemical  side  of  pharmacology  and  its  relation  to  physiological  chemistry, 
discovering  the  synthesis  of  hippuric  acid  from  glycocoll  and  benzoic 
acid,  and  determining  the  formula  of  histamine  and  nucleic  acid.  Above 
all  else  he  influenced  others,  his  pupils  perhaps  more  than  any  other  group 
being  responsible  for  establishing  the  science  of  pharmacology,  Hans 
Meyer  of  Vienna,  John  J.  Abel  of  Baltimore,  and  Arthur  Cushny,  for- 
merly of  the  University  of  Michigan,  now  of  London,  all  leaders  in 
the  new  science. 

In  America  pharmacology  has  made  great  strides.  Horatius  C. 
Wood  C)  of  Philadelphia,  a  pioneer  in  this  field,  bore  the  load  single- 
handed  in  the  earlier  days,  carrying  out  pharmacological  and  therapeutic 
researches  on  nitrites  and  hyoscine,  writing  prolifically  on  all  matters  per- 
taining to  the  use  of  drugs  and  on  many  other  fields  of  medicine.  With 
the  coming  of  Abel  and  of  Cushny,  chairs  of  pharmacology  were  created 
and  its  future  in  this  country  became  assured. 

So  rapid  has  been  its  progress  that  the  action  of  drugs  has  been  made 


838     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

the  basis  not  only  of  treatment  but  also  of  determining  the  state  of 
activity  of  certain  systems.  One  example  may  be  given  which  reveals 
in  a  remarkable  way  on  the  one  hand  the  complexity  of  the  mechanisms 
involved  in  physiological  functions,  and  on  the  other  the  exactness  with 
which  the  seat  of  action  of  drugs  can  be  determined. 

Through  the  researches  of  Gaskell,  Langley  (^)  and  others,  much 
light  has  been  shed  upon  the  structure  and  functions  of  the  sympathetic 
nervous  system.  Although  it  presides  over  many  of  the  vital  functions, 
the  importance  of  its  role  has  but  recently  been  ascertained.  In  disclosing 
these  revelations,  drugs  have  been  of  the  greatest  assistance,  and  have 
resulted  in  the  use  of  the  so-called  pharmaco-dynamic  tests. 

In  opposition  to  the  animal  nervous  system,  which  is  under  the  control 
of  the  will,  stands  the  vegetative  system  C)  through  the  efferent  branches 
of  which  are  supplied  organs  whose  function  is  not  so  controlled.  The 
vegetative  system  consists  of  two  varieties  of  nerves,  the  sympathetic 
and  the  autonomic  or  craniosacral  (Fig.  i).  Almost  all  the  internal 
organs  are  supplied  by  fibers  from  each  class  which  act  antagonistically, 
thereby  resulting  in  tonicity  of  a  smooth  muscle,  and  normal  function  of 
glandular  structures. 

Excessive  activity  on  the  part  of  either  system  results  in  a  rather 
characteristic  train  of  manifestations.  Since  their  actions  are  antago- 
nistic, stimulation  of  one  system  produces  effects  analogous  to  inhibition 
of  the  other.  The  vegetative  system  as  a  whole  is  influenced  by  nicotine, 
which  at  first  stimulates  and  later  paralyzes  all  its  ganglia  and  post- 
ganglionic fibers.  On  the  other  hand,  certain  drugs  affect  only  one 
system  or  the  other.  Thus  epinephrin  acts  only  on  the  sympathetic  nerve- 
endings,  exciting  them,  and  hence  produces  the  same  effect  on  the  various 
organs  as  stimulation  of  their  sympathetic  nerve  supply.  Epinephrin 
therefore  causes  vasoconstriction  (coronary  and  pulmonary  excepted), 
strengthening  and  accelerating  the  heart,  dilating  the  pupils,  and  increas- 
ing secretion  of  the  salivary  glands,  while  on  the  functions  of  the 
stomach,  intestines,  and  bladder,  where  the  sympathetic  normally  inhibits, 
it  causes  relaxation. 

Certain  other  drugs  affect  the  autonomic  exclusively  without  in- 
fluencing in  any  way  the  sympathetic  system.  The  drugs  acting  on  the 
autonomic  system  are  atropine  which  paralyzes  it  and  pilocarpin  and 
muscarin  which  stimulate  it.  Thus  muscarin  and  pilocarpin  cause 
miosis,  slowing  of  the  heart,  contraction  of  bronchial  muscles,  violent 
contraction  of  the  intestine,  and  secretion  of  true  glands,  while  atropin 
in  each  instance  causes  the  reverse  of  these  effects. 

By  the  therapeutic  application  of  epinephrin,  atropin,  and  pilocarpin, 
much  can  be  learned  concerning  the   functional   state  of   mechanisms 


W     "^       G 


H  ^ 


«3«] 


G..  coeliacum 


^- 


Auerbach's  plcxiis,  which  is 
stimulated  by  small  amounts  of  atropine; 
paralyzed  by  larger  amounts  of  atropine. 


^  Vagus  plexus  on  the  serosa 


Inhibiting  nerve-endings  which 
are  excited  by  epinephrin. 


Vagus  nerve-endings  which  are  excited 
by  pilocarpine,  choline,  etc.,  and  para- 
lyzed by  small  amounts  of  atropine. 


Fig.  2    Diagram  of  the  Innervation  of  the  Intestine. 

After  Meyer  and  Gottlieb,  "Die  Experimentelle  Pharmacologic," 
Urban  and  Schwarzenberg,  Berlin. 


P.  839I 


FACTORS  OF  PROGRESS  IN  THERAPY  839 

innervated  by  these  systems.  Through  their  use  the  responsibihty  of 
sympathetic  or  autonomic  systems  for  certain  manifestations  can  be 
determined.  According  to  the  preponderance  of  the  sympathetic  or 
autonomic  systems  generally,  individuals  are  classified  as  sym- 
patheticotonic  or  vagotonic.  It  is  true,  however,  that  these  pharma- 
cological facts  have  led  to  speculations  in  clinical  medicine  which  on 
the  whole  have  caused  confusion  rather  than  clarity. 

The  effects  of  these  drugs  can  best  be  exemplified  by  consideration 
of  their  action  on  the  muscles  of  the  intestine.  Movements  of  the  intes- 
tines are  of  three  kinds;  (a)  pendulum,  which  results  in  division,  mixing, 
and  moving  about  of  intestinal  contents;  (b)  true  peristalsis,  with  con- 
traction above  and  relaxation  below,  the  result  of  distention  or  chemical 
stimulation;  resulting  in  the  moving  downward  of  the  intestinal  con- 
tents; and  (c)  rolling  movements,  violent  contractions  of  the  small 
intestine  involving  considerable  stretches  of  it,  described  by  Meltzer  and 
by  him  ascribed  to  increased  vagus  tone  with  simultaneous  inhibition  of 
the  splanchnic  sympathetic.  These  movements  are  under  the  control  of 
Auerbach's  plexus  or  Langley's  "enteric  system,"  stimulation  coming 
through  the  vagus  and  hypogastric  and  inhibition  through  the 
splanchnics.     (Fig.  2.) 

Drugs  which  act  upon  the  autonomic  and  sympathetic  systems 
markedly  affect  intestinal  movements,  pilocarpin,  muscarin  and  physo- 
stigmine  stimulating  contraction  which  may  be  violent  and  tonic  in 
character,  and  atropin  inhibiting  contraction  through  paralysis  of  the 
vagus  terminals.  These  results  are  effected  by  direct  action  on  the  vagus 
terminals  and  not  through  Auerbach's  plexus  and  the  sympathetic  ter- 
minals. Auerbach's  system  is  composed  of  branches  from  the  vagus  and 
sympathetic,  and  acts  automatically  and  independently.  On  stimulation 
it  accelerates  and  strengthens  normal  waves  of  contraction,  but  does  not 
result  in  tonic  contractions  or  cramps.  On  this  plexus,  atropin  exerts 
in  small  doses  at  first  a  stimulating  and  later  in  larger  doses  a  paralyzing 
effect,  just  as  do  nicotine  and  strychnine. 

The  sympathetic  system  is  the  inhibitor,  acting  antagonistically  to 
the  plexus  and  to  the  vagus  nerve.  It  is  subject  to  stimulation  by  nicotine 
and  epinephrine,  both  of  which  cause  relaxation  of  the  intestinal  wall. 
The  innervation  of  the  muscles,  together  with  the  seat  and  character  of 
the  action  of  various  drugs  are  graphically  depicted  in  Fig.  2. 

The  action  of  atropin  is  interesting  because  of  the  existence  of  two 
points  of  action.  Thus,  therapeutically,  it  may  cause  either  relaxation 
of  spasm  or  increased  normal  peristalsis,  depending  on  the  condition  of 
tonicity  obtaining  at  the  time  of  administration.  In  lead  poisoning 
and  vagotonia,  for  instance,  where  tonicity  is  greatly  increased  through 


840     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

stimulation  of  the  vagus,  atropine  causes  relaxation  through  its  action 
on  the  vagus.  Through  the  relaxation  of  spasm,  normal  intestinal  move- 
ments and  activity  supervene.  In  this  manner  atropin  may  act  as  a 
purgative  or  a  supplement  to  other  purgatives  in  the  conditions  of 
increased  intestinal  tonicity  resulting  in  constipation.  On  the  other  hand, 
administered  when  increased  tone  or  spasm  is  absent,  atropin  tends  to 
increase  peristalsis  through  its  influence  on  Auerbach's  plexus.  Thus  is 
explained  pharmacologically,  a  fact  long  recognized  clinically,  namely, 
that  belladonna  or  atropin  in  small  doses  are  valuable  in  conjunction 
with  purgatives  in  some  spastic  types  of  constipation.  In  large  doses 
they  paralyze  the  intestines.  The  dose,  therefore,  must  be  adapted  to 
the  existing  condition  and  must  remain  small  if  intestinal  peristalsis  is 
desired. 

(3)    The  Chemical  Basis  of  Pharmacology* 

One  approaches  this  subject  with  trepidation,  yet  with  hope.  Much 
is  known  in  a  fragmentary  way;  there  are  isolated  instances  of  the 
effects  of  constitution  on  pharmacological  action.  Definite  laws  can  be 
laid  down  in  some  instances  as  to  the  character  of  changes  in  action, 
resulting  from  changes  in  constitution  along  determined  lines.  Still  in 
a  broad  practical  sense  but  little  is  known  about  it  at  the  present  time. 
We  have  but  a  vision  of  the  "  promised  land." 

As  the  atom  and  molecule  are  fundamental  to  the  understanding  of 
chemistry,  so  cell  and  molecule  are  fundamental  to  chemotherapy.  In  the 
progress  of  science,  naturally  form  received  attention  first,  later  function, 
and  lastly  constitution  and  chemical  reactions.  The  body  consists  of 
cells  of  different  sizes,  shapes,  and  groupings,  all  of  which  are  afifected 
by  disease.  The  cells  perform  functions  of  diverse  nature  in  relation  to 
which  there  exists  great  interdependence  of  activity.  Their  functions  are 
also  affected  by  disease.  The  cells  live.  Their  life  depends  upon  chemical 
activities,  and  the  function  is  associated  with  or  controlled  by  chemical 
reactions,  and  these  in  turn  are  affected  by  disease. 

From  the  standpoint  of  chemotherapy,  the  living  cell  and  the  chemical 
molecule  are  brought  into  relation.  The  cell  must  be  looked  upon  as  a 
participating  seat  of  microchemical  reactions.  In  it  are  chemicals  under- 
going reactions  resulting  in  the  development  of  forces;  to  it  are  being 
added  constantly  new  chemicals  resulting  in  modification  of  reactions  and 
of  forces.    Products  result  which  are  valuable  to  the  cell,  and  hence  are 

*  Two  excellent  works  exist  on  this  subject,  "Die  Arzneimittel-Synthese."  by 
Sigmund  Frankel,  Julius  Springer,  Berlin,  1906,  and  "  The  Chemical  Basis  of 
Pharmacology,"  by  Francis  and  Fortesque-Bricksdale,  Edward  Arnold,  London,  1908, 


FACTORS  OF  PROGRESS  IN  THERAPY  841 

retained,  or  to  other  cells,  when  they  are  transported  elsewhere,  or  which 
are  simply  by-products  or  end-products,  in  which  event  they  are  thrown 
out  from  the  cell  for  excretion.  The  living  cell  is  a  series  of  electric 
cells  or  a  laboratory,  in  which  reactions  are  going  on  constantly,  and  in 
which  forces  are  being  created.  The  medicament  is  a  new  chemical 
reagent  and  the  effect  of  these  new  chemical  molecules  on  the  natural 
process  is  the  factor  to  be  determined. 

In  order  to  obtain  a  comprehensive  grasp  of  these  activities  of  a  cell 
and  of  the  effect  of  new  extraneous  chemical  molecules  upon  them,  it  is 
necessary  to  understand  both  factors;  namely,  the  constitutional 
reactions  and  normal  activity  of  the  cells  on  the  one  hand,  and  on  the 
other  the  constitution  and  relationships  of  the  new  chemical  molecule 
added. 

The  key  to  pharmacological  action  of  a  drug  is  found  in  the  chemical 
constitution  and  activities  underlying  and  associated  with  cell  function. 
Unfortunately  this  is  where  medical  science  is  lacking.  Knowledge  of 
the  ultimate  physics  and  chemistry  of  cells  is  wanting.  Consequently,  at 
present,  investigation  in  chemotherapy  is  limited  in  character,  permitting 
only  modification  relative  to  the  extraneous  chemical  molecules  and  the 
study  of  the  effects  of  these  changes  in  modifying  gross  physiological 
functions. 

From  the  foregoing,  it  is  obvious  that  in  order  to  act  upon  the  cells, 
contact  or  incorporation  is  essential.  In  this  connection  Ehrlich  {^'^) 
has  emphasized  the  importance  of  distribution  of  chemicals  and  in  the 
same  connection  has  introduced  his  conceptions  which  involve  chemo- 
ceptors.  The  distribution  varies  with  different  drugs  and  is  more  or  less 
accepted  by  the  profession  as  a  matter  of  course.  On  the  other  hand,  it 
constitutes  a  vital  process  which  is  a  determining  factor  in  pharma- 
cological action.  Localization,  seat  of  action,  and  channels  of  excretion 
are  not  matters  of  chance,  but  are  determined  by  the  chemical  constitution 
of  the  medicament.  In  order  that  a  drug  may  act  on  the  cell,  it  must  be 
anchored  by  a  receptor. 

Cells  possess  receptors  of  several  types,  nutritive-ceptors,  chemo- 
ceptors,  and  immuno-ceptors.  Foods,  drugs,  and  toxins  contain  hapto- 
phore  groups  which,  in  the  event  they  fit  the  receptors,  attach  the  molecule 
to  the  cell.  But  some  differences  exist  in  the  mechanism  involved  with 
these  varying  substances.  The  nutritive  molecule  is  assimilated  by  the 
cell.  The  molecule  of  toxin  is  capable  of  setting  up  processes  of  immuni- 
zation which  result  in  excessive  production  of  receptors  which  are  thrown 
off  into  the  circulation,  where  they  constitute  antibodies  capable  of 
uniting  with  and  rendering  inert  the  toxic  molecule.  Chemoceptors 
unite  with  haptophores  of  drugs  and  thus  render  them  capable  of  action. 


842      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

but  they  are  not  found  as  a  rule  in  excess,  that  is,  they  do  not  exist  as 
antibodies,  free  in  the  circulation.  It  also  appears  that  the  receptors  may 
be  only  partially  occupied  by  the  drugs,  in  which  condition  they  are  still 
susceptible  to  union  with  closely  allied  drugs;  i.e.  atoxyl  and  arsenious 
acid.  Thus  a  trypanosome  may  be  resistant  to  atoxyl  and  its  affinity 
for  arsenic  blunted,  yet  if  it  be  subjected  to  a  surcharge  of  arsenious 
acid,  it  is  afifected.  It  is  possible  in  other  instances  that  some  radicle  or 
side  chain  constitutes  the  haptophore  group  and  is  responsible  for  fixation, 
as  for  instance  the  acetyl  group  (CH3CO)  in  arsacetin,  which  renders 
the  latter  effective  in  atoxyl-fast  strains.  On  the  other  hand,  receptors 
may  be  completely  fixed  by  one  drug,  and  also  by  closely  allied  drugs, 
for  instance,  trypanosomes  made  fast  for  both  atoxyl  and  arsenious 
acid  may  be  fast  also  for  antimony. 

The  physical  and  chemical  properties  of  the  cell  and  of  the  medica- 
ment determine  the  presence  or  absence  of  affinities.  The  nature  of 
these  affinities  or  receptors  is  important.  The  variants  must  be  con- 
sidered, (a)  the  chemical,  and  (b)  the  protoplasm  of  the  cell,  the  rela- 
tion being  mutual  or  reciprocal. 

(a)  Chemical  Factors. — From  the  chemical  viewpoint,  many  factors 
must  be  considered.  Variation  in  valence  markedly  affects  the  chemical 
properties.  The  fundamental  observation  in  Ehrlich's  work  consisted 
in  recognizing  that  it  was  trivalent  and  not  pentavalent  arsenic  which 
destroyed  trypanosomes.  The  striking  difference  in  the  toxicity  of 
HgsClz  and  HgCL,  and  of  CO2  and  CO  affords  ample  proof  of  the 
importance  of  valence. 

The  chemical  constitution  or  formula  is  another  determining  factor. 
Knowledge  of  the  empirical  formula  is  necessary  but  does  not  suffice. 
Complications  arise  in  the  possibility  of  different  arrangements  of  the 
atoms  in  the  molecule.  Thus  two  substances  may  have  the  same 
empirical  formula,  the  same  number  of  C,  H,  and  O  atoms,  but  yet  be 
different  in  every  respect.  Thus  C2H4O2  represents  acetic  acid,  but  it 
also  represents  formic  ester,  two  very  different  substances.  Chemistry 
teaches  us  that  CsHgO  may  represent  two  substances,  OHCH2CH2CH3, 
normal  propyl,  alcohol,  or  (CH3)2CH-OH  isopropyl  alcohol,  and  that 
these  substances  have  different  chemical  and  physical  properties.  Prop- 
erties depend  on  chemical  grouping  within  the  cell,  so  that  knowledge  of 
structural  formulae  is  also  necessary. 

Pasteur  demonstrated  that  there  were  several  kinds  of  tartaric  acid, 
C4H6O6,  dextro,  laevo,  meso,  and  racemic.  He  demonstrated  that  atoms 
may  have  different  space  arrangements,  and  in  so  doing  he  founded 
stereoisomerism.  The  stereoisomeric  arrangement  also  markedly  affects 
chemical  and  pharmacological  properties.     As  the  molecule  of  hydro- 


FACTORS  OF  PROGRESS  IN  THERAPY  843 

carbons  increases  in  size  and  the  complexity  multiplies,  the  possibilities 
for  different  substances  increases  tremendously,  thus  C13H28  offers 
more  than  800  possibilities.  Consequently  the  difficulty  of  as- 
signing constitutional  formulae  has  become  increasingly  great.  But 
structural  formulae  are  essential  as  the  basis  of  study  of  pharmacological 
action.  Radicles  play  a  great  role  as  haptophores  or  as  powers  affecting 
chemical  reactions.  Affinities  are  "  constitutional "  properties  in  the 
terms  of  Ostwald. 

Solubility  is  of  the  utmost  importance.  Toxicological  measures  fre- 
quently consist  of  attempts  to  render  solutions  of  drugs  insoluble,  and 
antidotes  frequently  owe  their  efficacy  to  their  power  of  precipitating 
the  poison  before  its  absorption.  Unless  in  solution,  incorporation  in 
the  cell  is  most  difficult.     Incorporation  is  necessary  for  action. 

The  methods  of  administration  of  certain  drugs  are  determined  by 
the  factor  of  volatility,  thus  chloroform  and  ether  owe  much  to  their 
volatility,  which  permits  a  ready  means  of  administration,  and  also 
considerable  control. 

(b)  The  Protoplasm  of  the  Cell. — The  chemical  structure  of  the 
molecule  of  most  drugs  is  simple  compared  with  that  of  the  cell.  It 
is  the  protoplasm  of  the  cell  that  offers  the  chief  difficulty  in  solving 
the  problem  of  the  action  of  drugs.  Proteins  are  so  infinitely  complex 
that  attempts  to  consider  them  chemically  are  not  profitable  at  present. 
The  chemistry  of  the  living  cell  is  beyond  the  science  of  today.  At 
present,  however,  our  main  interest  centers  on  the  living  cell,  and  par- 
ticularly on  the  properties  of  cells  which  make  them  subject  to  influence 
by  drugs.  What  constitutes  the  chemoceptors?  A  silk  fiber  stains 
with  picric  acid,  a  nerve  fiber  takes  up  methylene  blue  intravitam,  a 
certain  nerve  responds  to  an  alkaloid.  Ehrlich  discards  the  possibility 
of  surface  attraction  and  of  absorption  in  staining  of  fibers  and  limits 
consideration  to  two  factors,  (a)  insoluble  salt  combinations  as  ad- 
vanced by  Knecht,  and  (b)  solid  solutions  of  van't  Hoff  as  outlined 
by  Witt.  In  the  first  instance  lanugic  acid  from  wool  fiber  and  nucleic 
acid  of  nuclear  substances  may  precipitate  basic  dyestuff  from  solutions. 
Methylene  blue  as  a  vital  stain  is  thus  thrown  down  by  the  plant  as  the 
insoluble  tannate.  An  example  of  solid  solution  is  seen  in  silk  stained 
with  rhodarium  which  fluoresces.  This  must  be  a  solution  since 
rhodarium  is  not  fluorescent  except  in  solution.  It  is  assumed,  there- 
fore, that  the  dye  forms  a  homogeneous  mixture  with  the  silk  fiber; 
i.e.  it  is  in  the  form  of  a  solution.  "  The  same  dye  often  produces 
different  tints  in  various  kinds  of  fibers.  This  is  analogous  to  the  fact 
that  the  same  substance  often  dissolves  in  different  solvents  in  entirely 
different  tints." 


844     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

The  factors  which  determine  the  formation  of  the  dye  are  proper- 
ties of  both  the  drugs  and  the  cell.  Mutual  relationships  must  exist.  It 
is  impossible  to  separate  them  absolutely  as  factors  apart,  since  mutual 
forces  are  encountered  in  the  drugs  and  in  the  cell. 

(a)  Colloidal  State. — What  relationships  exist  in  the  living  cell? 
In  gelatin  there  are  "  vesicular  and  sponge-like  gels."  In  the  former, 
the  liquid  phase  exists  in  the  form  of  separate  droplets,  each  surrounded 
by  a  continuous  film  of  solid  phase.  In  the  latter,  the  two  phases  are 
reversed,  the  solid  phase  is  in  the  form  of  a  network  of  threads,  while 
the  liquid  phase  is  continuous.  The  former  is  the  ordinary  gel  from 
which  fluid  can  be  expressed  only  with  the  greatest  difficulty;  the  latter, 
obtained  through  the  action  of  formaldehyde,  is  a  gel  from  which  water 
is  readily  expressed.  This  problem  has  been  elucidated  by  the  system 
of  solvents  so  nicely  demonstrated  in  the  work  of  Clowes  Bayliss  (") 
who  says,  *'  Protoplasm  in  the  living  state  has  the  properties  of  a  liquid 
system,  containing,  however,  particles  of  solids  and  amounts  of  immis- 
cible liquids  in  a  freely  moving  state."  The  relationship  of  dyes  and 
drugs  to  the  various  phases  must  enter  into  consideration  of  pharmaco- 
logical action. 

(b)  Surface  Condensation  or  Adsorption. — The  structure  of  proto- 
plasm is  such  as  to  present  large  surfaces  which  furnish  excellent 
ground  for  the  play  of  surface  forces  so  important  in  life  processes. 
Drugs  may  be  held  in  contact  with  cells  by  adsorption. 

(c)  Changes  in  Cell  Membrane. — The  surface  layer  of  cells  fre- 
quently present  relatively  limited  permeability,  through  which  the 
cell  is  protected  from  other  cells  and  from  surrounding  fluids.  The 
character  of  this  membrane  and  its  permeability  plays  a  role 
in  the  action  of  chemicals.  Solvents  of  this  membrane  make  ingress 
possible. 

(d)  Velocity  of  Diffusion. — The  passage  of  substances  into  a  cell 
must  be  considered  a  factor  in  some  instances.  Thus  Straub  showed 
that  muscarin  in  the  heart  of  aplysia  had  no  effect  when  the  concentra- 
tion within  the  cell  reached  the  concentration  outside  of  the  cell.  Only 
during  the  period  of  concentration  in  the  cell  was  the  drug  active.  Nat- 
urally, in  addition,  the  physical  and  chemical  properties  such  as  solu- 
bility, volatility,  surface  condensation,  or  adsorption  and  electrical 
charges  are  important. 

Velocity  of  diff^usion,  solubility,  and  volatility  of  drugs,  colloidal 
states,  surface  condensation,  and  electric  charges  of  both  drugs  and  cells 
all  play  a  role  in  determining  fixation,  rate  of  absorption,  physiological 
action,  and  excretion  of  the  drugs  by  the  cell. 

The  cell  protoplasm  plays  a  great  role  in  solubility  and  hence  in 


FACTORS  OF  PROGRESS  IN  THERAPY  845 

making  substances  available.  The  narcotic  value  of  a  drug  depends 
principally  on  its  solubility  in  lipoid  substances.  Generally  speak- 
ing, "  the  most  powerful  narcotics  are  those  which  are  most  soluble 
in  oil  and  least  soluble  in  water."  Lipotropic  substances  are  also  neuro- 
tropic. The  Overtun-Meyer  theory  of  narcosis  attempts  to  explain  the 
entrance  of  drugs  to  the  nerve  cells  on  this  basis :  "  They  gain  access  to 
the  cells  of  the  cerebral  nervous  system  owing  to  their  solubility  in  cell 
lipoids  in  which  these  cells  are  particularly  rich."  Gradations  in 
narcotic  power  are  due  to  the  presence  of  groups  which  increase  the 
partitive  coefficient;  i.e.  which  render  the  derivatives  more  soluble  in 
such  fatty  substances.  Physical,  as  well  as  purely  chemical  factors 
play  a  role.  In  the  cell  proteins,  lecithins,  salts  and  water  exist  in  a 
physicochemical  combination,  and  the  drugs  affect  this  physicochemical 
equilibrium.  This  conception  is  constantly  attracting  more  attention. 
A  chemical  may  be  anchored  to  a  cell  very  quickly,  yet  it  may  not 
manifest  its  effect  immediately,  for  instance,  tetanus  toxin  is  anchored 
eight  minutes  subsequent  to  intravenous  injection,  at  which  time  anti- 
toxins are  usually  ineffective  and  fail  to  protect,  though  given  simultane- 
ously with  the  toxin  they  protect  perfectly. 

These  theories  explain  the  presence  of  the  drug  in  the  cell,  but  not 
its  mechanism  of  action.  According  to  Oscar  Loew,  general  poisons 
react  on  protoplasm  in  four  ways :  oxidation,  catalysis,  salt  formation, 
and  substitution. 

The  first  includes  oxidizing  agents  such  as  H.Oo  and  ozone,  perman- 
ganates, etc.  The  catalytic  agents  are  represented  by  the  aliphatic 
narcotics.  Iodine  in  relation  to  metabolism  is  considered  by  some  to 
act  as  a  catalizing  agent  only.  Salt  formation  is  dependent  upon  the 
amphoteric  character  of  protein,  and  involves  acids  bases,  alkaline 
earths,  and  salts  of  heavy  metals.  The  fourth  group  includes  a  large 
number  of  substances  capable  of  reacting  with  aldehydes  and  amines, 
such  as  hydroxamines,  phenyl  hydroxamines,  hydroxylamines,  anilines, 
free  ammonia,  phenols,  especially  the  amido  phenols,  and  HCN 
and  H3S. 

Amines  particularly  are  active,  primary  amines  other  than  of  the 
aliphatic  series  being  more  active  than  secondaries,  which  in  turn  are 
more  active  than  tertiary.  Thus  NHo  groups  are  important  radicles  in 
basic  dyes,  OH  in  acid  dyes,  where  they  are  known  as  auxochromes. 
These  active  radicles  react  with  labile  groups  of  living  protoplasm  and 
thus  affect  the  living  cell.  These  labile  groups  disappear  with  the  death 
of  the  cell,  subsequent  to  which  such  reactions  cease.  Loew  believes 
that  "  toxicity  increases  pari  passu  with  reactivity." 

Ehrlich   launches  many   arguments  against  synthesis   in   cells,   and 


846     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

states  that,  in  his  belief,  it  rarely  occurs  in  relation  to  substances  foreign 
to  the  cell.  He  admits,  however,  that  it  does  occur  in  relation  to  vinyl- 
amine,  which  produces  a  peculiar  papillary  nephritis,  an  ethyl  amide 
group  entering  the  protoplasmic  molecule. 

Specific  or  special  poisons  act  only  on  certain  classes  of  organisms. 
In  this  group  he  considers  toxins  and  antitoxins,  specific  poisons,  alka- 
loids, and  indirect  poisons  which  interfere  with  oxidations  such  as 
HCN.  In  the  mind  of  the  writer,  no  reasons  exist  for  placing  alkaloid 
and  specific  poisons  in  this  special  class. 

In  selective  action  two  factors  naturally  suggest  themselves ;  namely, 
(a)  reactions  which  play  such  an  important  role  in  relation  to  staining, 
and  acid  and  basic  dyes,  and  (b)  the  degree  of  oxygen  saturation. 
Unquestionably  these  are  determining,  or  at  least  secondary  factors  in 
many  instances. 

In  relation  to  pharmacological  action  and  absorption  and  excretion 
it  is  interesting  to  revert  to  an  observation  made  by  Ehrlich,  and  which 
he  refers  to  repeatedly;  i.e.  that  the  sulphonic  group  introduced  into 
neurotropic  substances  renders  them  inert  from  the  point  of  view  of 
the  nervous  system.  The  introduction  of  a  sulphone  group,  SO3H 
(=50.),  renders  many  substances  inert;  i.e.  it  changes  the  distribution 
of  the  drug  in  the  organism. 

Sulphonation  also  plays  a  role  in  relation  to  excretion  of  drugs. 
Thus  phenolphthalein,  C2H14O4 

/C6H4OH 
C;^C6H40H 

C6H4        O 

when  introduced  into  the  body  is  excreted  by  both  liver  and  kidneys. 
If  chlorine  is  introduced  in  the  phenol  rings  (^')  C^) 

^C6H40H 
C^CeHiOH 

/\ 

C6CI4         O 

\    / 
CO 

it  is  excreted  entirely  by  the  liver.     If,  on  the  other  hand,  it  is  sul- 

phonated  (") 

^C6H40H 
C^C6H40H 

C6H4^       .0 

SO, 


FACTORS  OF  PROGRESS  IN  THERAPY  847 

it  is  excreted  entirely  by  the  kidneys.  Sulphonation,  therefore,  has 
resulted  in  a  different  channel  of  excretion,  and  in  one  of  the  most 
striking  instances  of  specificity  known  to  medical  science.  Sixty  to 
eighty  per  cent,  of  the  drug  on  intravenous  injection  is  excreted  in  one 
hour  by  the  normal  kidney.  In  this  connection  a  striking  affinity  exists 
for  the  dye  by  the  renal  cells;  so  striking  that  practically  all  of  the 
dye  is  taken  up  by  the  kidney  in  the  course  of  an  hour.  But  the  dye 
is  not  fixed.  Here,  then,  we  have  an  affinity  without  action  on  the 
cell,  the  drug  being  picked  up  and  excreted.  The  explanation  is  difficult. 
Unquestionably  many  other  similar  instances  exist  in  relation  to  ex- 
cretion. 

Instances  of  Chemical  Constitution  Controlling  Pharmacological  Action 

In  1859  Stahlschmidt  (^^)  demonstrated  that  strychnine  loses  its 
tetanizing  action  when  a  methyl  group  is  introduced  and  the  new  com- 
pound assumes  a  curare-like  action.  Crum,  Brown,  and  Eraser  in  1868, 
in  view  of  the  ammonium  base  formed  in  this  reaction,  investigated 
other  similar  bases  derived  from  alkaloids,  brucine,  morphine,  and 
thebaine,  and  discovered  that  all  quaternary  ammonia  bases  exert  a 
curariform  action,  paralyzing  motor  nerve-endings.  This  was  the  be- 
ginning of  rational  synthetic  pharmacology  and  called  attention  to  the 
relation  of  pharmacological  action  to  chemical  constitution. 

Ehrlich  (^^)  in  1898  enumerated  five  important  instances  selected 
from  the  whole  field  of  therapy  where  a  relationship  was  established 
between  chemical  constitution  and  pharmacological  action.  ( i )  The 
antipyretic  action  of  aniline  and  amido  phenol  derivatives  is  definitely 
related  to  the  amount  of  pure  amido  phenol  (NH2C0H4OH)  split  off  in 
the  organism.  Prevention  of  the  splitting  off  of  this  substance  by  sub- 
stitution as  in  amido-acetophenon  (NHaCeHiCOCHg)  renders  the  sub- 
stance ineffective  as  an  antipyretic. 

(2)  Antipyretics  become  ineffective  through  the  introduction  of  salt- 
forming  acid  radicles  such  as  SO3H  and  COoH.  Thus  the  antipyretic 
action  of  acetanilid,  CoHnNHCOCH,,  is  destroyed  by  the  introduction  of 
acetic  acid,  CH3COOH,  which  results  in  C6H,N(COCH3)CH,C03H. 
Similarly  the  sulphone  derivative,  CsHgNHCOCHaSOaH,  no  longer  af- 
fects temperature.    Phenacetine 


/OC2H5 
C6H4\NHCOCH 


likewise  is  no  longer  an  antipyretic  if  sulphonated  or  carbonated.  The 
reason  for  this  is  found  in  the  prevention  of  splitting,  resulting  in 
free  p-amido  phenol. 


848      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 


OH 

which  is  essential  for  antipyretic  action. 

(3)  In  the  pyridin  series,  C5H5N,  the  hydrated  products  act  more 
strongly  than  the  parent  substances. 

(4)  The  benzoyl  radicle  (CeHsCO)  is  the  anesthesiophore  group  of 
cocaine,  and  many  of  its  substitution  products.  Cocaine,  C17H21NO4, 
breaks  up  on  hydrolysis  as  follows : 

Ci.H^iNO^  +  2  H.O  =  C^Hi^NOs  +  CeHsCOOH  4^'  CH3OH. 

If  the  ecgonine  methyl  ester  is  substituted  by  other  radicles  than  benzoyl, 
for  instance,  succinic  acid  (dReOi),  the  resulting  chemical  has  no 
anesthetic  properties.  Substitution,  leaving  the  benzoyl  radicle  intact, 
has  been  the  basis  of  many  of  the  cocaine  substitutes. 

(5)  Recognition  of  the  relation  of  ethyl  groups  to  hypnotic  action 
of  drugs  resulted  in  the  preparation  of  more  effective  hypnotics.  The 
more  ethyl  groups  in  di-sulphonic  bodies,  the  more  active  becomes  this 
property.  In  sulphonal  there  are  two,  (CH3)2  C  (S02C2H5)2,  and  in 
trional  three,  CH3(C2H5)C(S02C2H5)2-  They  are  also  present  in 
amylene  hydrate  and  ethyl  urethane.  The  ethyl  group  is  also  active 
in  phenacetine,  C2H5OC6H4NHCOCH3,  in  holocaine, 

OCH. 


0 


NiCNHCfiH^OCgHs 
CH3 

Thus  alcohol  itself  exerts  a  soporiferous  action,  as  do  the  alcohol  radicles 
in  various  hypnotics,  sulphonal,  trional,  amylene  hydrate,  and  in  certain 
anesthetics. 

Obviously,  it  is  impossible  to  more  than  touch  upon  certain  rules  or 
generalities  *  relating  to  the  subject.  The  aliphatics  as  a  group  are  not 
as  active  pharmacologically  as  the  aromatic  hydrocarbons,  which  are  also, 
in  addition,  more  reactive  from  the  chemical  point  of  view. 

*  For  detailed  discussion  of  the  chemical  basis  of  pharmacology,  the  reader  is 
referred  to  the  excellent  volume  of  Francis,  and  Fortescue  Bricksdale,  which  is  the 
best  publication  of  its  kind  known  to  the  writer.  From  it  are  taken  many  selected 
examples  of  the  relation  of  pharmacological  action  to  chemical  structure  here  presented. 


FACTORS  OF  PROGRESS  IN  THERAPY  849 

Aliphatic  Hydrocarbons 

Lauder  Brunton  called  attention  to  the  fact  that  the  action  of  the 
aliphatic  series  is  chiefly  on  nerve  centers,  first  stimulation,  then 
narcosis,  and  predominantly  on  sensory  nerves.  The  lower  members 
of  the  fatty  series,  especially,  are  preponderantly  stimulating  and 
anesthetic  to  nerve  centers.  Schmiedeberg  recognized  two  classes : 
(a)  the  alcohol  and  chloroform  group,  which  includes  most  of  the  nar- 
cotics of  the  aliphatic  series,  gaseous  and  fluid  hydrocarbons,  the 
monatomic  alcohols,  their  ethers,  ketones,  aldehydes,  and  their  halogen 
derivatives;  (b)  the  ammonia  derivatives,  which  exercise  a  con- 
vulsant  action  on  the  cells  of  the  cord.  Conversion  from  trivalent  to 
pentavalent  nitrogen  is  accompanied,  as  already  stated,  by  marked 
changes  in  physiological  effect,  a  curare-like  action  replacing  the  con- 
vulsant. 

The  introduction  of  alkyl  groups  into  aliphatic  compounds  generally 
increases  the  physiological  effect.  But,  as  the  molecule  increases,  the 
solubility  and  volatility  decreases,  and  the  compound  becomes  relatively 
inert.  As  a  rule,  substitution  of  the  H  of  the  hydroxyl  by  an  alkyl 
group  results  in  an  ether,  an  entirely  different  substance  with  different 
properties  and  increased  volatility.  Under  such  conditions  ethyl  alcohol 
is  converted  into  ethyl  ether,  C2H5OC2H5,  while  glycerine  becomes  the 
glycerine  ester,  which  has  narcotic  properties.  On  replacing  the  H  atom 
of  ammonia  with  alkyl  groups,  amines  (primary,  secondary,  and  tertiary) 
result  with  decreased  toxicity,  but  as  the  tertiary  amines  are  converted 
into  ammonium  compounds  the  toxicity  is  markedly  enhanced.  An  alkyl 
group  entering  a  carboxyl  group,  converting  the  organic  acid  into  an  ester, 
naturally  confers  new  properties;  thus,  oxalic  acid  yields  the  narcotic 
di-ethyl-oxylate. 

The  ureids  are  important  in  the  animal  economy  and  in  therapy. 
Uric  acid  represents  dibasic  ureids,  the  end  stage  of  nuclear  metabolism. 
Xanthine, 


NH— C  =  0 
1           1 

1           { 
CO      c 

NH  — ( 

:  -NH 

> 

:-N 

one  of  the  intermediate  products,  is  somewhat  inert.  By  the  introduc- 
tion of  methyl  groups,  one,  two,  or  three,  into  the  amide  radicles,  new 
pharmacological  properties  appear.    Thus  we  obtain  theobromine, 


850     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

/ 

HN  — C 

I         I  /^^' 

CO    C  — N^ 

I        II  CH 

CH3N  — C  — N^ 


and  caffeine, 


N— C 


I        II         X^°« 
CO    C— N< 

I       II         ^CH 
N— C— N***^ 

CHs 

both  of  which  are  excellent  diuretics  and  cardiac  stimulants. 

Unsaturated  open  chain  hydrocarbons  are  more  toxic  than  the  sat- 
urated, and  are  extremely  reactive.  The  double  bond  offers  enlarged 
opportunities  for  reaction.  Toxicity  is  multiplied  many  fold.  To  this 
class  belongs  neurine, 

(CH3)3NCH:CH2 
OH 

a  dehydration  product  of  cholin,  which  is  itself  not  markedly  toxic. 

Aromatic  Hydrocarbons 

Generally  speaking,  these  are  more  reactive,  have  more  marked 
pharmacological  action,  and  tend,  as  pointed  out  by  Brunton,  to  affect 
motor  rather  than  sensory  nerves,  and  to  produce  convulsions  and 
paralysis.  Benzene  acts  on  cerebral  centers  producing  somnolence  and 
also  .paresis  of  muscles  and  tremor.  Diphenyl  and  its  compounds  tend  to 
be  more  inert.  Napthalene  is  relatively  more  toxic  and  is  said  to  slow 
respiration  and  decrease  metabolism. 

Substitution  of  H  of  the  ring  nucleus  of  benzene  by  alkyl  groups 
tends  to  decrease  reactivity  and  toxicity,  and  to  modify  pharmacological 
properties.  In  anilines  it  increases  toxicity,  while  in  phenols  it  increases 
the  antiseptic  value  and  decreases  toxicity.  Alkyl  substitution  of  the 
OH  of  phenol  renders  the  new  compound  practically  inert,  while  the 
same  procedure  in  resorcin  results  in  increased  toxicity.  Alkyl  substi- 
tution in  the  NH2  group  of  anilines  depresses  the  convulsant  action, 
whereas  in  benzamides  and  salicylamides  it  increases  it.  Alkyl  sub- 
stitution in   the  carboxyl  chains  of  aromatic  compounds   changes  the 


FACTORS  OF  PROGRESS  IN  THERAPY 


851 


character  of  the  substance,  thus  salicylic  acid  becomes  the  methyl  ester, 
methyl  salicylate,  or  oil  of  wintergreen.  Phenols  become  inert  ethers. 
Substitution  may  occur  in  the  H  atoms  of  the  ring  or  in  the  groups 
which  substitute.  H.  Kendricks  and  Dewar  laid  down  a  rule  that  the 
introduction  of  H  into  cyclic  bases  invariably  increases  pharmacological 
action  and  toxicity.  Dujardin,  Beaumetz,  and  Bardel  studied  the  influ- 
ence of  side  chains  on  benzene  compounds  and  concluded  that:  (a)  those 
with  OH  are  antiseptic;  (b)  those  with  amide  or  acid  amide  groups 
are  hypnotic;  (c)  those  containing  both  an  amide  and  alkyl  group  are 
analgesic.  These  rules  must  not  be  taken  as  absolute,  but  they  hold  in 
the  majority  of  cases  and  constitute  an  intelligent  basis  for  changes  in 
structure. 

The  influences  of  certain  changes  in  relation  to  benzene  seems,  per- 
haps as  well  as  any  other  example,  to  demonstrate  the  effect  of  struc- 
ture on  function: 


CH 


CH 


.CH 


CH  VCH 
CH 

(benzene)  produces  somnolence  and  lethargy; 

CHg 


(toluene)  is  antiseptic; 


CHoOH 


(benzyl  alcohol)  is  a  local  anesthetic; 

OH 


(phenol)  has  acid  properties  and  is  antiseptic  and  toxic; 


852     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

(cresol),  the  substitution  here  has  increased  the  germicidal  efficiency, 
while  the  toxicity  is  not  increased,  at  least  not  in  the  same  ratio. 
Cresoles  possess  advantages  as  antiseptics. 

COOH 


(benzoic  acid),  is  non-toxic  and  slightly  antiseptic; 

OH 
/\COOH 


(salicylic  acid)  is  mildly  toxic,  antiseptic,  and  has  specific  properties 
against  streptococcus  infection  (fever,  pain),  the  corresponding  meta 
and  para  derivatives  having  neither  of  these  properties;^ 

OH 

/\  COOCH3 


(methyl  salicylate)  has  the  same  general  properties  as  salicylic  acid. 
Substituted  methyl  radicles  yield  other  substances  with  similar  proper- 
ties, methyl  oxymethyl  (mesotan),  mono  glycol  (spirosal), 

OH 
/\  COOCeHs 

(salol).  Such  phenyl  salicylates  on  decomposition  yield  active  phenols 
for  local  action.  Consequently  their  use  has  been  attempted  as  intestinal 
antiseptics.     Instead  of  the  phenyl  group,  naphthyl  may  be  substituted. 

OCH3CO 
/VCOOH 


(aspirin)  has  the  same  general  effect  as  salicylic  acid,  but  the  analgesic 
and  antipyretic  effects  are  greater,  and  the  local  irritating  effect  is  less 


FACTORS  OF  PROGRESS  IN  THERAPY 


853 


marked.      Salicin,    C13H18O7,    yields   on    hydrolysis,    a    glucoside    and 
saligenin, 


OH 


CH.OH 


(saligenin)   is  a  local  anesthetic  with  one-half  the  toxicity  and  twice 
the  anesthetic  effect  of  benzyl  alcohol,  according  to  Hirschfelder. 


SOpNaNCl 


(benzene  sodium  sulpho  chloramine,  or  chloramine-B)  in  which  the  NCI 
group  is  held  responsible  for  its  marked  antiseptic  property. 


Heterocyclic  Hydrocarbons  and  Alkaloids 
The  important  members  of  this  group  are : 


n 


N 
Pyridin 


CH2 
HaO  /\  CH2 


H2C  \/  CH2 
NH 

Piperidine  or 
hexa  hydro  pyridine 


HC—  CH 

II  II 

HC        CH 

NH 

Pyrrol 


HoC 


CH, 


H2C\/CH 
NH 

Pyrrolidin 


^^\A 


W 

N 
Quinolin 


/\A> 


\A^N 

Iso- 
quinolin 


These  enter  into  the  consideration  of  the  chemistry  of  alkaloids, 
and  therefore  are  of  great  medical  interest. 

Pyrrol  somewhat  resembles  benzene  in  its  action.     Pyridin  is  the 

nucleus,  thus 

CH 
CH  ^  CH 


CH 


and  is  least  toxic,  while  piperadine  and  pyrrol,  and  pyrrolidin  are  more 
active.  The  larger  the  chain,  the  more  active  the  compound,  as  a 
rule.  The  entrance  of  an  alkyl  group  definitely  increases  activity,  tetra- 
methyl  pyridin  being  several  times  as  potent  as  pyridin  itself,  and 
exhibiting  somewhat  different  action.  Quinolin  is  closely  related  to 
pyridin. 

Alkaloids  are  complex  nitrogenous  substances  with  basic  properties, 
possessing  a  pyridin  or  a  condensed  pyridin  nucleus. 

Atropine,  C17H23NO3. 


854     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 
Atropine, 

H2  H  H2 

C  — C    C  CH2OH 

I         I  / 

N— CH2CHO  —  COCH 
I  I  \ 

C  — C    C  ,      CeHg 

is   an   ester.     When  hydrolized  it  yields   tropine,   a  condensation   of 
piperadine  and  pyrrolidin  rings,  and  tropic  acid : 

CHaaNOs  +  H2O  =  GHibNO  +  GHioO,. 

Tropine  has  the  formula, 

CH2      CH         CH2 
N  — CH3CHOH 

CHg      CH  CH2 

tropic  acid, 

CH2OH 
CeHsCH 

^COOH 
Tropine  differs  from  ecgonin  by  one  carboxyl  group  (vide  infra), 
consequently,  atropin  and  cocaine  are  very  closely  related  chemically. 
As  a  matter  of  fact,  they  give  almost  identical  constitutional  effects  so 
far  as  cerebrum,  heart  (vagus  terminals),  temperature,  blood  pressure, 
and  eyes  are  concerned.  Atropin,  however,  paralyzes  the  nerves  to 
unstriped  muscles  and  secreting  glands,  while  cocaine  has  a  more  marked 
anesthetic  effect  and  causes  in  addition  peculiar  foamy  degeneration  in 
the  liver  cells  of  mice,  first  recognized  by  Ehrlich. 

The  substitution  of  other  acids  for  tropic  acid  may  be  made,  result- 
ing in  other  tropines.    Thus  homatropin  is  a  tropine  of  mandelic  acid, 

/OH 
CeHgCH 

\COOH 

The  relation  of  tropic  and  mandelic  acid  is  evident.  The  more  rapid 
onset,  and  the  shorter  duration  of  action  of  homatropin,  is  due  to  more 
rapid  absorption  and  excretion. 

Cocaine,  C17H21NO4,  is  represented  by : 

CH2-  CH  —  CHCOOCH3 

I  N      CH3CHOC6H5CO 

CH2—  CH  —    CH2 


FACTORS  OF  PROGRESS  IN  THERAPY  855 

(benzoyl  ecgonium  methyl  ester).     On  hydrolysis  it  splits  up  into  a 
base,  ecgonine,  methyl  alcohol,  and  benzoic  acid: 

C17H21NO4+  2H20=  C9H15NO3+  CeHBCOOH  +  CH3OH. 
Ecgonine,  as  already  stated,  is  closely  related  to  tropine,  and  has 
the  formula: 

CHo— CH CHCOOH 

I  I 

N-CHs     CH-OH 

I  I 

CH2— CH  —  CH2 

The  most  important  pharmacological  attribute  of  cocaine  is  its 
power  of  producing  analgesia  and  anesthesia.  This  is  not  due  to  the 
ecgonine  group,  but  usually  to  the  "  presence  and  relative  position  of  the 
two  substituting  groups.  The  (CH3COO)  group  is  essential  to  the 
action  of  cocaine  as  activating  the  carboxyl  group.  The  importance  of 
the  benzoyl  group  is  shown  by  the  fact  that  in  its  absence  no  anesthetic 
effect  occurs,"  and  moreover  many  other  substances  containing  it,  exert 
the  same  effects.  "  In  ecgonine  derivatives  it  cannot  act  without  simul- 
taneous replacement  of  the  carboxyl  group  by  a  COOR  group,  and  the 
presence  of  the  two  groups  alone  in  such  a  simple  substance  as  benzoic 
methyl  ester,  CeHgCOOCHs,  is  sufficient  to  produce  local  anesthesia." 

As  already  indicated,  Ehrlich  referred  to  the  CeHsCO  group  as 
the  anesthesiphore  radicle.  The  NCCHg)  group  is  an  "  auxotox,"  and 
on  it,  depends  the  liver  degeneration.  Thus  it  is  possible  to  analyze 
cocaine  into  its  more  important  radicles  and  to  explain  rationally  its 
various  properties  on  the  grounds  of  its  chemical  constituents. 

Opium  Alkaloids. — Opium  contains  several  alkaloids,  the  more  im- 
portant being  morphine,  papaverin,  codeine,  narcotine.  narcine,  and 
thebain.  Their  properties  have  been  known  for  a  long  period.  Recently, 
through  the  work  of  Macht  (''),  our  knowledge  of  their  nature,  mechan- 
ism, and  cause  of  action  has  been  greatly  enhanced. 

Macht  began  his  studies  by  investigating  the  action  of  the  opium 
alkaloids  individually,  and  in  combination  with  each  other  on  the 
respiratory  tract.  He  demonstrated  (a)  that,  on  the  bronchi,  narcotine 
and  papaverin  are  dilators,  as  are  also  morphine  and  codeine,  but  to  a 
less  extent.  The  other  alkaloids  have  no  such  effects.  Morphine  and 
narcotine  act  antagonistically;  (b)  that  morphine  and  codeine  are 
sedative  or  depressant,  while  narcotine,  papaverin,  narcine,  and  thebain 
are  stimulating  to  the  respiratory  centers;  and  (c)  that  the  combined 
action  of  opium  alkaloids  is  a  combination  of  their  individual  effects. 

He  later  studied  quantitatively  the  analgesic  effects  of  the  six  princi- 
pal  opium   alkaloids   and    found   the   effective    dose    to   be:   morphine 


856     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

(lomg.)'  papaverin  (40),  codeine  (20),  narcotin  (30),  narcine  (10), 
thebain  (10),  respectively.  On  combining  morphine  and  narcotin, 
meconates  (narcophin),  the  analgesic  power  is  greater  than  the  arith- 
metical sum  of  the  effects  of  its  constituents.  Therefore,  true  synergism 
exists  in  this  combination. 

Later  studies  followed  dealing  with  the  action  through  the  sacral 
autonomics  of  several  of  these  alkaloids  and  other  drugs  on  the  ureter. 
An  effort  w^as  then  made  to  determine  the  relation  of  the  action  of  these 
alkaloids  to  their  chemical  structure.  Morphine  belongs  to  the  pyridine 
phenanthrene  group, 


papaverin  and  narcotin  to  the  benzyl  isoquinolin  group, 


Morphine  was  found  to  increase  contraction  and  tonicity,  and  papa- 
verin to  inhibit  contraction  and  to  induce  relaxation.  In  combinations 
such  as  pantopon,  the  benzoyl  isoquinolin  radicle  action  predominates. 
This  group  was  therefore  investigated,  with  the  result  that  the  relation 
of  the  relaxation  to  the  combination  of  a  double  nucleus;  namely,  the 
combination  of  an  isoquinolin  with  a  benzyl  component  was  discovered. 
The  isoquinolin  radicle  itself  does  not  produce  relaxation.  The  benzyl 
group,  therefore,  was  considered  responsible  for  the  inhibitory  and 
sedative  action  of  papaverin  and  narcotin.  Confirmation  was  obtained 
in  the  action  of  peronin,  which  is  a  benzyl  morphine.  Unlike  morphine 
and  its  other  derivatives,  it  produces  inhibition.  An  hypothesis  was 
advanced  that  the  inhibitory  action  of  papaverin  on  the  ureter  is  due 
to  the  benzyl  constituent  and  that  the  stimulating  action  of  morphine  is 
due  to  the  piperidin  constituent.  Extension  of  the  work  to  the  gall 
bladder  yielded  confirmatory  results,  but  the  contraction  of  the  gall 
bladder  produced  by  morphine  and  analogous  bodies  is  slight  compared 
with  that  of  the  ureter. 


FACTORS  OF  PROGRESS  IN  THERAPY  857 

Recognition  of  the  role  played  by  the  benzyl  group  in  the  relaxation 
of  unstriped  muscles  led  him  to  further  investigation  of  the  properties 
of  the  benzyl  nucleus,  and  to  the  discovery  of  its  value  as  a  local  anes- 
thetic.    Benzyl  alcohol  or  phenmethylol  has  the  formula,  CrHgO  or 

,  CH2OH 


In  nature  it  occurs  in  jasmine  and  as  an  ester  in  the  balsams  of  Peru 
and  of  Tolu,  Compared  with  the  well  known  local  anesthetics  it  pos- 
sesses powerful  local  anesthetic  properties,  and  at  the  same  time  is  rela- 
tively non-toxic.  Clinically  in  one  to  four  per  cent,  solution  it  is  an 
effective  safe  local  anesthetic. 
The  esters,  benzyl  acetate 

CH       CH 

CH3CO2H2C   <^        ^CH 

CH      CH 
and  benzyl  benzoate 

CH     CH 

HsCfiCQ^HaC^        ^CH 
CH        CH 

were  next  studied,  and  found  to  act  much  like  papaverin.  They  are 
metabolized,  are  low  in  toxicity,  and  have  been  employed  by  Macht  with 
excellent  results  in  conditions  of  excessive  peristalsis  of  smooth  muscle. 

Macht,  through  analyzing  the  structure  of  various  alkaloids,  has  suc- 
ceeded in  determining  the  properties  of  the  various  groups,  and  through 
the  recognition  of  the  importance  of  the  benzyl  group  has  placed  in  the 
hands  of  the  profession  a  valuable  local  anesthetic,  and  two  general 
sedatives  capable  of  overcoming  undue  contraction  of  smooth  muscles. 

Quinine,  C20H24N2O2.     Quinolin 


is  the  structural  skeleton  of  the  active  principle  of  quinine  and  also  of 
nux  vomica.  It  is  an  antiseptic,  and  decreases  metabolic  rate.  But  it  is 
irritating  to  the  gastric  intestinal  tract,  and  cannot  be  used  internally. 
It,  and  its  isomers,  have  many  properties  in  common  with  pyridine. 
Quinine  is  oxymethyl  cinchonin  with  the  formula  as  ascribed  by  Skraup : 


858     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

CH 

CH2(4NCH-CH:CH2 

CH2 
I 

CH2 

H0C\!/CH2 

I     N 
CH2 

OCH, 


Quinoline  itself  has  but  little  antipyretic  action  in  malaria,  has  but 
little  effect  on  the  parasite,  and  in  pneumonia  has  no  effect  on  the  fever. 

At  the  present  time  it  has  not  been  determined  in  which  radicle  the 
potency  of  quinine  resides.  It  is  not  thought  to  be  in  the  quinoline  con- 
stituent. Discussion  has  been  centered  about  the  vinyl  (CH:  CH2) 
group  in  the  side  chain.  Hunt  (^*)  has  shown,  however,  that  the  altera- 
tion of  the  vinyl  group  in  quinine  to  CH2CH3  or  to  CHOHCH3,  and 
CHCICH3  does  not  appreciably  influence  its  effect  against  infusoria. 

Cupreine  has  come  into  some  prominence  in  medicine  because  of  its 
effect  in  pneumonia.  Quinine  is  methyl  cupreine.  Morgenroth  demon- 
strated that  in  pneumonia  of  mice  ethyl  hydroxy  cupreine  exercises  an 
effect  little  short  of  specific. 

Influence  of  Metabolism 

Drugs  after  administration  may  undergo  great  alterations.  Given 
by  mouth,  changes  occur  frequently  before  the  tissues  are  reached.  In 
the  mouth  there  is  no  change,  as  a  rule.  In  the  stomach  the  free  HCl 
tends  to  increase  the  solubility  of  basic  substances,  and  to  break  down 
anilides.  In  the  intestine  the  bile  and  pancreatic  juice  cause  saponifica- 
tion of  fats,  and  esterification  also  increases  the  solubility  of  some 
organic  acids.  Generally  speaking,  the  drugs  are  changed  in  such  a 
way  that  they  become  less  toxic. 

The  chief  changes,  however,  occur  in  the  blood  and  tissues.  Syn- 
thesis, oxidation,  and  reduction  are  the  three  processes  best  understood. 
In  synthesis,  combinations  occur  with  sulphonic,  glycuronic,  and  glyco- 
collic  acids,  the  end-results  being  most  frequently  urea  and  its  derivatives, 
glycuronates,  sulphocyanides.  and  sulphocarbolates.  These  processes  are 
of  great  importance  in  the  process  of  detoxification.  Oxidation  affects 
many  drugs  in  the  same  manner  as  it  does  foodstuffs,  the  end  products 
being  CO,  and  H2O.  Partial  oxidation  facilitates  further  oxidation. 
The  primary  alcohols  oxidize  to  aldehydes  and  acids,  the  secondary  to 


FACTORS  OF  PROGRESS  IN  THERAPY  859 

ketones,  while  tertiary  alcohols  tend  to  break  down  into  simpler  com- 
pounds. The  nature  of  the  process  is  but  incompletely  understood.  In 
the  aromatic  hydrocarbons  the  ring  is  usually  left  intact,  oxidation  af- 
fecting the  groups  substituting  the  H  atoms  of  the  ring.  Benzoic  acid 
frequently  results,  combines  with  glycocoll,  and  is  excreted  as  hippuric 
acid.  Oxidation  of  hydrogen  in  the  beta  position  sometimes  yields  beta 
oxybutyric  acid,  diacetic  acid,  and  acetone. 

Reduction  is  effected  in  the  body  with  more  difficulty  and  instances 
are  relatively  rare,  but  chloral  is  reduced  to  the  corresponding  alcohol 
and  excreted  as  a  glycuronate,  and  some  nitro-bodies  are  reduced  to  cor- 
responding amines. 

Vital  Force  has  been  a  subject  of  controversy  for  long  periods. 
With  a  clearer  understanding  of  various  forces,  the  types  of  forces  are 
disappearing.  Radiant  energy  is  now  classed  as  a  branch  of  chem- 
ical science,  and  chemical  and  electrical  energy  are  probably  one  and 
the  same  form  of  energy.  In  considering,  as  one  must,  the  mutual  rela- 
tionship of  the  drug  and  cell,  involved  in  pharmacological  action,  it 
appears  that  we  have  many  theories  involving  facts  of  very  diverse 
nature.  In  all  probability  a  combination  of  forces  plays  a  role.  Barger 
and  Dale  (^^)  say,  "The  least  unsatisfactory  view  seems  to  us  to  be 
that  which  regards  the  existence  of  stimulant  activity  as  dependent 
on  the  processes  of  some  chemical  property,  the  distribution,  and,  in 
the  main,  the  intensity  of  activity  as  due  to  a  physical  property." 

(4)   Specific  Chemotherapy  and  Experimental  Therapy 

The  surest  and  usually  the  shortest  approach  to  the  specific  treat- 
ment of  any  condition  is  through  the  experimental  reproduction  of  the 
disease  in  animals  and  through  the  subsequent  application  of  experi- 
mental therapy.  Science  is  built  on  experimentation.  Nature's  secrets 
are  well  shielded.  Facts  must  be  pried  from  her  through  experimenta- 
tion, scientific  methods  constituting  a  fulcrum.  But  in  the  human,  only 
the  most  limited  experimentation  is  possible.  Human  life  is  too  valua- 
ble, only  in  desperate  conditions  are  desperate  remedies  justified.  But 
desperate  conditions  do  not  permit  of  recovery  as  a  rule  even  though 
the  treatment  be  correct  in  principle. 

The  value  of  human  life  has  retarded  progress  in  therapy  by  blocking 
the  channels  through  which  science  ordinarily  flows.  In  consequence 
the  physician  is  limited  in  his  practice  to  well  established,  usually  time- 
honored,  partially  effective,  non-harmful  measures.  His  responsibility 
is  heavy,  and  he  adheres  to  the  ancient  principle,  "  primum  non  nocere." 
Science  is  not  built  on  isolated  observations,  but  on  laws  established 


86o     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

through  the  study  of  behavior  in  repeated  experiments  under  conditions 
accurately  controlled. 

Although  desperate  remedies  are  rarely  justified,  they  are  frequently 
needed.  Once  laws  governing  their  action  have  been  established,  the 
element  of  danger  can  be  quantitatively  determined,  and  in  some  in- 
stances practically  eliminated.  These  laws  can  only  be  established 
through  ascertaining  the  proximity  of  death,  which  means  that  death 
itself  must  result  in  certain  instances.  This  obviously  eliminates  human 
experimentation  from  consideration,  and  hence,  we  resort  to  lower  ani- 
mals. With  the  experimental  disease,  all  the  tools  of  science  are  made 
available,  the  only  limitations  existing  being  those  of  the  investigator. 

Aside  from  pharmacology,  experimental  therapy  centers  about  three 
major  fields,  specific  chemotherapy,  immunotherapy,  and  organotherapy. 
Each  of  these  constitutes  an  independent  branch  of  science. 

Specific  Chemotherapy  of  Trypanosomiasis 

This  field  of  science  was  created  almost  entirely  through  the  labors 
of  Paul  Ehrlich  (^"),  which  culminated  in  the  introduction  of  salvarsan 
("  606  "),  and  of  neosalvarsan.  The  character  of  the  work  involved,  the 
underlying  principles  covered,  and  the  factors  leading  to  practical  results 
can  be  best  presented  by  quotations  from  his  preface  in  his  masterpiece, 
"  Spirilloses  and  Their  Treatment."  "  A  medicinal  substance  can  only 
act  upon  the  bodily  system  into  which  it  has  been  incorporated.  The 
object  of  the  researches  was  to  find  a  distinct  curative  type  and  to  im- 
prove it  more  and  more  by  means  of  transformation  and  substitution. 
Whereas,  formerly  the  substances  were  offered  to  the  medical  man  by 
the  chemist  for  testing  purposes,  the  conditions  could  now  be  reversed, 
and  the  chemotherapeutist  could  give  the  chemist  points  which  lead  to 
the  desired  recovery  of  genuine  curative  substances."  In  this  way  he 
substituted  science  for  chance.  "  It  was  far  more  a  question  of  putting 
the  principles  of  action  of  medicine  on  a  therapeutic  basis,  the  study  of 
what  I  should  like  to  describe  as  the  therapeutic  biology  of  parasites. 
The  success  of  my  work  depends  upon  the  conception  of  chemoceptors 
obtained  in  these  researches."  In  relation  to  syphilis,  he  further  says, 
"  It  was  only  by  knowledge  of  the  parasite  which  causes  the  disease, 
and  through  the  possibility  of  transferring  it  to  animals,  that  experi- 
mental chemotherapeutic  work  is  rendered  possible,  while  the  specific 
blood  reaction  is  indispensable  in  determining  the  genuine  curative 
action." 

The  discovery  of  trypanosomes  (^^)  as  the  cause  of  disease  in  ani- 
mals, surra  of  camels  by  Evans  (1880),  nagana  by  Bruce,  dourine  by 
Rouget  (1894),  and  their  occurrence  in  humans,  by  Button  (1901),  and 


FACTORS  OF  PROGRESS  IN  THERAPY  86i 

their  etiological  relationship  to  sleeping  sickness  by  Castellani  (1903), 
led  to  the  experimental  production  of  these  diseases  in  animals  and  to 
attempts  at  their  cure. 

Laveran  in  1903  demonstrated  that  arsenious  acid  exerted  a  marked 
toxicity  on  trypanosomes,  but  was  incapable  of  effecting  a  cure  in  in- 
fected animals.  Thomas  (^^)  of  the  Liverpool  School  of  Tropical  Medi- 
cine used  atoxyl  in  experimental  trypanosomiasis  with  good  results, 
and  sought  other  forms  of  arsenic,  less  toxic  for  the  host.  He  con- 
sidered atoxyl  to  be  the  sodium  salt  of  the  anilid  of  meta-arsenic  acid, 
with  the  formula 

ONa 
^        ^NH  — As  =  0 
ONa 

Ehrlich,  who  had  previously  tried  and  discarded  atoxyl  in  his  studies 
on  trypanosomiasis,  interested  himself  in  it  again  subsequent  to 
the  report  of  Thomas  and  Brienl  ('**).  With  the  assistance  of 
Bertheim  {'''),  he  investigated  atoxyl  chemically,  being  puzzled  by  cer- 
tain of  its  reactions.  He  finally  concluded  that  it  was  not  an  anilid^  of 
meta-arsenic  acid,  but  the  sodium  salt  of  para-amino-phenyl-arsenic 
acid, 

ONa 

ONa 

This  discovery  was  of  the  greatest  significance  to  medical  science, 
and  constituted  the  basis  of  the  work  which  resulted  in  the  development 
of  chemotherapy.  Thomas  made  definite  progress  by  establishing  the 
value  of  atoxyl,  and  in  calling  attention  to  the  desirability  of  searching 
for  arsenicals  with  greater  toxicity  for  parasites  and  with  decreased 
toxicity  for  the  host.  Ehrlich,  on  the  other  hand,  found  the  key  to 
greater  progress  in  recognizing  the  true  nature  of  atoxyl.  The  first 
conception  of  it,  as  a  fixed  analid,  admits  of  no  great  changes  in  the 
molecule,  whereas  its  true  formula  reveals  the  possibility  of  the  prepara- 
tion of  a  whole  series  of  compounds.  The  NHo  group  can  be  acetylated, 
benzoated,  can  be  substituted  by  halogen  or  by  hydroxyl  radicles.  In 
this  way  arsacetin  resulted  with  the  formula, 

OH  ^ 

COCH3NH  ^         )>As  =  0 
I 

oa 


862     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

This  was  found  to  possess  decided  advantages  over  atoxyl,  being  more 
stable  and  somewhat  less  toxic,  while  equally  parasititropic.  It  was 
used  clinically  in  sleeping  sickness  with  fair  results. 

Ehrlich's  efforts  were  next  directed  to  determining  the  method  in 
which  atoxyl  acts.  In  vitro  it  was  not  strikingly  toxic  to  trypanosomes, 
but  after  administration  serum  containing  it,  it  was  extremely  toxic 
acting  in  dilution  of  1/120,000  according  to  Koch.  Ehrlich  conceived  the 
idea  that  the  increase  in  toxicity  after  administration  was  due  to 
reduction  of  the  arsenic;  i.e.  that  the  arsenic  became  trivalent 
instead  of  pentavalent.  In  this  connection,  the  following  facts  were 
established : 

O 
NH2<(        ^As— OH 

OH 
(atoxyl)  does  not  kill  in  five  per  cent,  solution  in  one  hour; 

O 

OH  ^       y  As—  OH 

^      \ 

OH 

(p.  oxyphenyl  arsenic  acid)  kills  in  one  to  two  per  cent,  solution; 

<~>As=0 
(arsenoxide)  kills  in  1/100,000  in  one  hour; 

OH  <^       y  As=  0 

(paroxyphenyl  arsenoxide)  kills  in  1/1,000,000  in  one-half  hour.  Re- 
duction has  resulted  in  increased  toxicity,  as  it  has  done  in  many  other 
instances,  CO  being  more  toxic  than  CO2  and  HCN  than  HCNO. 
Ehrlich  decided  that  the  toxic  body  concerned  in  the  death  of  the 
parasite  was  not  atoxyl  but  the  reduced  form  of 

OH  <^>       ^As=0 

Salvarsan  can  be  made  directly  from  atoxyl.  It  is  easier,  however, 
to  start  with  paroxy-phenyl-arsenic  acid 

O 

OH  <^^        y  As  =  OH 

OH 


FACTORS  OF  PROGRESS  IN  THERAPY  863 

When  properly  treated  with  nitrous  acid,  this  yields  a  compound,  meta- 
nitro-paroxy-phenyl-arsenic  acid, 

OH 

On    further    reduction,    this    yields    meta-amido-paroxy-phenyl-arsenic 
acid, 

NH2  O 

H0<(       )>As-OH 
OH 

and  later  meta  amido-para-oxyphenyl  arsinic  oxide. 

NH2 
0H<^^        ^As  =  0 

which  in  turn  can  be  further  reduced  to  dioxy-diamido-arseno  benzol, 

NH2  NK2 

OH  <(       y  As=As  <^        y  —  OH 

The  reduced  form  (R  —  As  =  As  —  R)  is  much  less  toxic  for  the  host 
than  R  —  As  =  O. 

Salvarsan  is  marketed  in  vacuum  tubes  in  order  to  prevent  oxida- 
tion, which  readily  occurs  on  exposure,  and  results  in  great  increase  in 
toxicity.  By  the  addition  of  hydrochloric  acid,  it  is  readily  converted 
into  the  acid  salt,  NH2HCI.  By  the  addition  of  NaOH,  it  is  neutralized, 
and  forms  the  alkaline  base 

NH2  NH2 

NaO<(         ^As=As<^         )>  ONa 

which  is  the  form  in  which  it  is  administered.     It  is  locally  irritating, 
and  therefore  given  now  exclusively  by  the  intravenous  route. 

Neosalvarsan,  or  "  914,"  was  later  introduced  by  Ehrlich,  being  some- 
what less  toxic,  and  decidedly  less  irritating  locally.  It  is  obtained 
from  salvarsan  by  the  addition  of  formaldosulphoxylate.  A  sulphoxyl 
group  has  the  formula  SO  OH,  is  derived  from  the  sulphoxyl  acid 
(HSOOH),  and  corresponds  to  the  carboxyl  group  COOH.  Salvarsan 
combines  with  sodium  formaldosulphoxylate  (HCOHOSNa),  which  is 


864     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

a  condensation  product  of  H2SO2  (sulphoxylic  or  hyposulphurous  acid) 
and  formaldehyde  (HCOH).    Neosalvarsan  has  the  formula, 

NH2 NHCHgO-OSNa 

0H<^        ^As=As<^        )>0H 

and  being  readily  soluble   in  water  and  locally  non-irritant,  may  be 
injected  subcutaneously  or  intramuscularly. 

The  work  of  Ehrlich  constitutes  one  of  the  most  remarkable  achieve- 
ments of  modern  medicine.  It  furnished  mankind  with  a  useful  remedy, 
demonstrated  in  a  most  practical  way  that  pharmacological  action  is 
dependent  upon  chemical  structure,  founded  chemotherapy,  and  re- 
vealed the  methods  whereby  the  creation  of  specific  treatment  is  made 
possible.  He  aimed  at  a  cure  in  one  dose  for  syphilis,  a  "  Therapia 
sterilisans  magna."  In  this  he  did  not  altogether  succeed,  but  he  pro- 
duced the  most  effective  remedy  yet  found  for  syphilis  and  blazed  the 
way  for  future  progress. 

Ehrliclis  Experiments  with  Trypanosomes. — Ehrlich's  own  animal 
experiments  were  conducted  on  trypanosomes,  and  it  was  from  these 
studies  that  he  acquired  the  principles  which  resulted  later  in  such 
great  discoveries. 

Mice  and  rats  are  readily  infected  with  many  species  of  trypano- 
somes, notably  T.  brucei,  T.  evansi,  T.  gambiense,  and  T.  equiperdum. 
Only  one  who  has  worked  with  trypanosomiasis  in  mice  can  appreciate 
the  opportunities  it  offers.  No  more  ideal  conditions  for  experimental 
therapy  can  be  desired.  A  given  strain  will  result  in  death  of  the 
animals  with  clock-like  regularity  as  to  time.  The  severity  of  the  infec- 
tion can  be  readily  ascertained  by  the  number  of  organisms  in  the 
blood,  as  can  also  the  rate  of  disappearance  of  the  organisms  as  the 
result  of  therapy.  In  addition,  large  numbers  of  animals  can  be 
handled  at  one  time,  the  only  facilities  needed  being  jars  or  cages, 
syringes,  glass  slides,  and  a  microscope.  The  technique  is  simplicity 
itself. 

Successful  treatment  furnishes  one  of  the  most  spectacular  phe- 
nomena ever  witnessed  in  the  field  of  therapy.  A  seriously  infected 
animal  lying  on  its  side,  too  weak  to  move,  and  with  as  many  as  two 
or  three  million  wriggling  trypanosomes  swarming  in  each  cubic  milli- 
meter of  blood,  may,  as  the  result  of  a  single  treatment,  return  within 
one  or  two  hours  to  absolute  normality  so  far  as  can  be  determined. 
With  the  disappearance  of  clinical  evidence  of  disease,  the  organisms 
disappear  entirely  from  the  blood.  This  transformation  within  an 
hour  from  death's  door  to  normality  must  be  seen  to  be  appreciated. 


FACTORS  OF  PROGRESS  IN  THERAPY  865 

The  principles  established,  and  the  laws  discovered  by  Ehrlich,  are 
as  follows : 

(i)  No  organism  is  affected  by  a  drug  unless  it  is  incorporated  in 
the  organism,  or  in  Ehrlich's  own  words,  "  Corpora  non  agunt  nisi 
fixata,"  which,  as  applied  to  chemotherapy,  must  be  interpreted,  "  para- 
sites can  only  be  destroyed  by  those  materials  for  which  they  have  a 
certain  affinity,  thanks  to  which  they  are  anchored  by  the  bacteria."  In 
this  connection,  he  assumed  the  presence  of  chemoceptors. 

(2)  Remedies  affect  both  the  host  and  the  parasite,  "only  those 
substances  can  be  employed  as  medicaments  in  which  organotrophy  and 
parasitotrophy  stand  in  proper  relation." 

(3)  By  accepting  the  best  remedy  available,  it  is  possible  through 
modification  of  its  constitution  to  change  its  properties,  and  further 
through  experimentation  and  control  it  is  possible  to  increase  para- 
sitotrophic  and  decrease  organotrophic  properties.  Thus  in  using  atoxyl 
as  the  basis,  the  potent  part  of  the  molecule  was  sought.  Trivalent 
arsenic  was  recognized  as  the  essential  factor.  Experimentation  proved 
the  possibility  of  increasing  the  toxicity  of  the  arsenic  of  the  molecule 
for  the  parasite,  and  by  working  on  the  benzyl  end  of  the  molecule  its 
toxicity  for  the  host  was  decreased.  Three  objects  were  attained, 
(a)  diminished  toxicity,  (b)  increased  action  on  the  parasite,  (3)  in- 
creased stability  of  the  combination. 

(4)  In  chemotherapy  experience  teaches  what  types  of  changes  in 
the  molecule  are  desirable,  in  other  words,  the  constitution  of  a  chemical 
determines  its  action,  and  the  laws  governing  organotrophic  and  para- 
sitotrophic  properties  can  be  recognized  and  utilized.  The  investigator, 
therefore,  must  direct  the  work  of  the  chemist,  suggesting  changes  in 
molecules  as  they  are  deemed  desirable,  and  not  testing  drugs  made  at 
random  by  the  chemist. 

(5)  Closely  allied  organisms  differ  in  pathogenicity,  in  the  acute- 
ness  of  the  resulting  disease  and  in  their  resistance  to  a  given  therapy, 
while  different  strains  apparently  causing  the  same  disease  also  may 
differ  from  each  other  in  the  same  respects.  For  example,  T,  lewisi 
and  T.  nagana  are  both  trypanosome  infections.  In  rats,  nagana  kills 
quickly  and  produces  a  fatal  disease,  which,  however,  responds  readily 
to  treatment  with  arsenic;  whereas  T.  lewisi,  which  occurs  naturally  in 
rats,  does  not  as  a  rule  prove  fatal,  and  is  totally  resistant  to  arsenicals. 
In  sleeping  sickness  in  Togoland,  many  cures  were  reported  with  arseno 
phenyl  glycin,  whereas  the  disease  as  encountered  in  the  Congo  was 
much  more  resistant. 

(6)  Cures  are  the  more  readily  obtained  the  earlier  the  treatment  is 
instituted. 


866      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

(7)  Relapses,  generally  speaking,  are  more  difficult  to  cure  than 
original  infections. 

(8)  Treatment  unsuccessful  in  the  first  instance  is  usually  unsuccess- 
ful in  repetition. 

(9)  Repeated  non-curing  treatments  frequently  result  in  progres- 
sively decreased  effects  on  the  parasite.  This  condition  Ehrlich  calls 
"  Festigkeit,"  which  indicates  that  the  strain  has  become  fast,  tolerant, 
or  resistant  to  the  drug. 

(10)  Repeated  non-curing  treatments  with  some  preparations  result 
in  the  development  of  hypersensitiveness  on  the  part  of  the  host  to  the 
medicament.  This  was  demonstrated  by  Kline,  Eckard,  Ullrich,  and  by 
Scherschmidt. 

(11)  As  the  ultimate  cure  by  one  dose  is  desirable  and  best,  a 
"  therapia  sterilisans  magna  "  should  be  sought. 

Ehrlich's  work  was  some  years  in  progress.  Collaborators  working 
clinically,  especially  in  Africa,  assisted  in  recognizing  and  establishing 
some  of  these  laws  so  that  clinical  as  well  as  laboratory  experience  con- 
tributed to  the  solution  of  the  problems.  Some  of  the  principles  enumer- 
ated were  recognized  independently  by  other  investigators. 

It  is  interesting  to  note  that  among  thousands  of  preparations  investi- 
gated by  Ehrlich  and  others,  only  four  groups  of  drugs  have  been  found 
which  are  strikingly  effective  in  trypanosomiasis.    These  are  as  follows : 

(i)  Certain  arsenicals,  arsenious  acid,  atoxyl,  arsacetin,  arseno- 
phenylglycin,  salvarsan,  and  neosalvarsan. 

(2)  Certain  azo  dyes;  (a)  trypan  blue, 

NH2    OH  , ^, .  OH      NH, 

/YX-N=N<         X         >N=N/\y\ 
CH3  CH3 

SOgNa'sA/  NaSOg  SOjNa  's./X/'NaSOa 

(b)   trypan  red, 

SO3 Na\/\/  NaSOs  SOgNa N/\/  NaSOj 

(3)  Certain  triphenyl  methane  basic  dyes,  parafuchsin,  pyronin,  and 
methyl  violet, 

OCl 
=N< 

(CH2)2 


FACTORS  OF  PROGRESS  IN  THERAPY  867 

(4)  Certain  antimony  preparations — antimony  tartrates  of  potas- 
sium and  sodium,  tartar  emetic,  K(SbO)  C4H4O6  +  y^H-^O,  p.  amino 
phenyl  stibinic  acid  (corresponding  to  atoxyl), 

OH 

NH2<(       ^Sb=Q 
OH 

Aniline  antimonyl  tartrate, 

C.H^Os 

Sb 
^OHCfiHyN 

Triamids  of  antimony,  thio  glycollate, 

SCH2CONH2 
Sb-SCHgCONHa 

SCH2CONH2 
Sodium  antimony  thioglycollate, 

SCHgCOONa 


0/ 

Sb 


SCHoCOO 


In  1909,  before  salvarsan  was  introduced.  Dr.  Abel  and  the  writer 
became  interested  in  chemotherapy  and  carried  out  experiments  through- 
out 1910  and  191 1.  Our  interest  centered  chiefly  on  the  effects  of  anti- 
monials  and  arsenicals  in  trypanosomiasis,  though,  as  will  be  seen,  later 
we  also  worked  with  spirilla  and  spirochetae.  The  trypanosomes  used 
were:  (i)  T.  brucei,  which  is  responsible  for  the  tsetse  fly  disease  which 
affects  horses,  mules,  donkeys,  and  cattle  in  Africa;  (2)  T.  evansi 
(strains  from  India  and  Mauritius),  which  produces  diseases  of  camels 
and  cattle;  (3)  T.  equiperdum,  which  affects  horses,  producing  dourine, 
instances  of  which  are  not  infrequent  in  this  country.  The  experimental 
animals  employed  were  rats,  rabbits,  and  dogs,  some  of  which  were  under 
observation  for  a  year  to  eighteen  months. 

Prior  to  these  studies,  antimony  had  been  tried  by  others,  Cushny 
first  suggesting  its  use.  Sodium  and  potassium  salts  of  antimony,  tar- 
trates (Thomson  and  Plimmer),  p.  amido  phenyl  stibinic  acid  (Breinl 
and  Nierenstein),  sodium  antimony  malate,  ethyl  antimonyl  tartrate 
(Collie,  Thomson,  and  Cushny),  and  aniline  antimony  tartrate  (Lav- 
eran)  ;  of  these,  tartar  emetic  proved  effective,  but  very  irritating  locally. 


868     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

The  substitution  of  an  alkyl  radicle  as  in  ethyl  antimonyl  tartrate  resulted 
in  definite  improvement  in  this  respect,  no  local  reactions  whatever  fol- 
lowing its  use,  and  cure  being  effected  in  seven  of  the  thirteen  rats 
treated. 

In  our  work  two  new  compounds  of  antimony  were  prepared,  the  tri- 
amide  of  antimony  thioglycollate,  and  sodium  antimony  thiogly collate. 
These  chemicals  were  tested  in  regard  to  their  efficacy  as  trypanocidal 
agents  in  several  series  of  inoculated  rats,  rabbits,  and  dogs. 

The  difference  in  the  virulence  in  the  diseases  produced  by  these 
strains  of  trypanosomes  is  striking;  T.  brucei  and  T.  evansi  killed  rats 
regularly  in  y2  to  84  hours,  while  that  of  Mauritius  and  of 
Dourine  were  much  less  virulent,  a  week  or  even  a  month  elapsing 
before  death  in  some  instances.  The  greatest  success  was  obtained 
with  the  triamide  of  antimony  thioglycollate  and  with  sodium  antimony 
thioglycollate. 

The  time  elapsing  between  the  date  of  inoculation  and  the  beginning 
of  treatment  is  the  most  important  factor  in  determining  the  results 
obtained.  The  longer  the  period  before  the  institution  of  treatment,  the 
less  the  degree  of  success  from  the  point  of  view  of  ultimate  cure;  the 
shorter  the  period,  the  greater  the  success.  These  drugs  administered 
24  hours  before  inoculation  failed  to  protect,  but  given  at  the  time  of 
the  inoculation  prevented  the  development  of  the  disease  in  every  instance. 
With  the  more  virulent  trypanosomes,  after  the  lapse  of  24  hours,  at 
which  time  organisms  were  beginning  to  appear  in  the  blood,  absolute  cure 
was  effected,  but  after  48  hours  or  more,  permanent  cure  was  infrequent. 
It  is  possible  to  drive  the  organism  from  the  blood,  so  that  subinoculations 
fail.  By  intermittent  graded  doses  it  is  possible  to  banish  the  organism 
for  prolonged  periods,  weeks  and  months,  but  on  the  withdrawal  of  treat- 
ment, they  reappear,  and  the  disease  rapidly  runs  its  course  unabated. 
This  can  be  accomplished  with  animals  which  would  otherwise  die  in  the 
course  of  an  hour  or  two.  During  the  time  that  the  blood  is  free,  the 
animal  appears  perfectly  normal  in  every  respect,  but  when  treatment  is 
continued  the  animal  after  some  months  finally  succumbs  to  the  effect  of 
the  antimony. 

Two  problems  present;  namely,  what  becomes  of  trypanosomes,  and 
how  do  relapses  develop? 

Examination  of  the  blood  subsequent  to  treatment  reveals  morpho- 
logic changes  in  the  trypanosomes.  They  become  slower  and  tardy  in 
their  movements.  Their  bodies  become  constricted,  and  they  take  on  a 
more  granular  appearance  such  as  is  commonly  seen  in  them  after  death, 
and  subsequent  to  the  death  of  the  host.  They  undergo  involution.  They 
finally  become  immotile;  the  flagella  often  become  detached  or  adherent 


FACTORS  OF  PROGRESS  IN  THERAPY  869 

to  the  centrosome.  The  process  is  associated  with  a  leucocytosis  as  a 
rule,  and  frequently  debris  from  the  organisms  can  be  demonstrated  in 
the  leucocytes.  Fever  is  present  in  some  of  the  larger  animals  during  the 
period  of  blood  infection,  and  this  may  disappear  promptly  upon  their 
disappearance  from  the  blood. 

Many  investigators  have  studied  the  tissues  of  various  organs  in  the 
attempt  to  find  a  lodging-place  for  the  trypanosomes  during  the  period  in 
which  the  blood  is  free.  Emulsions  of  various  organs  have  been  inocu- 
lated into  animals  and  controlled  by  utilizing  in  others  injections  of  blood 
from  the  heart.  The  claim  has  been  made  that  the  liver  and  bone  marrow 
harbor  the  organism  during  this  period,  and  that  inoculations  from  these 
tissues  are  frequently  successful  at  the  time  that  the  inoculations  from  the 
heart  blood  fail.  Others  question  this,  and  feel  that  the  further  removed 
from  relapse,  the  more  frequent  the  emulsions  from  organs  fail,  and 
that  only  immediately  subsequent  to  treatment,  and  just  before  relapse, 
is  it  possible  to  get  positive  results  from  organs,  at  which  time  the  blood 
is  also  positive  if  a  sufficient  amount  is  investigated. 

Ehrlich  believes  that  there  exists  during  this  period  a  true  immunity. 
This  immunity  is  specific  for  the  single  strain  concerned,  and  the 
immunity  reaction  may  be  utilized  for  the  differentiation  of  strains.  Sub- 
sequently, when  this  immunity  wears  off,  generally  speaking,  reinocula- 
tion  results  in  infections  analogous  in  every  respect  to  the  original  infec- 
tion. In  this  connection,  Terry  has  utilized  the  method  to  prove  that 
surra  of  India  and  surra  of  Mauritius  are  not  identical.  He  cures  surra 
of  India  in  a  mouse,  and  then  injects  a  mixture- of  surra  of  Mauritius 
and  surra  of  India,  and  proves  to  his  satisfaction  that  the  animal 
develops  only  surra  of  Mauritius.  Provided  this  is  true,  it  is  per- 
haps the  most  striking  instance  of  drug  specificity  known  to  medical 
science. 

Relapses  are  difficult  to  explain,  but  the  following  hypotheses  have 
been  suggested : 

(a)  That  on  treatment,  some  of  the  organisms  are  driven  into 
hiding  in  some  of  the  internal  organs,  where  they  are  not  subjected  to 
the  action  of  the  drug.  Subsequently  they  reappear  in  the  circulation 
and  cause  reinfection. 

(b)  That  not  all  trypanosomes  are  equally  susceptible  to  the  influence 
of  drugs,  and  that  the  more  resistant  organisms  persist.  This  is  strongly 
suggested  by  studies  of  the  action  of  drugs  on  trypanosomes  in  hanging 
drop  preparations.  After  the  vast  majority  of  organisms  are  killed,  it  is 
not  at  all  unusual  to  find  isolated  trypanosomes  still  very  active. 

(c)  That  trypanosomes  undergo  cycles  in  development,  and  that  they 
are  more  resistant  in  some  parts  of  the  cycle  than  in  others. 


870     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 


Drug  Resistance 

Tolerance. — During  the  course  of  the  work  with  trypan  red  and 
arsenicals  Ehrlich  and  his  collaborators  found  that  non-curative  doses, 
which  at  first  sufficed  to  cause  disappearance  of  the  organisms  from  the 
blood,  lost  this  power  subsequently  in  the  same  animal.  Larger  doses  at 
first  gave  some  effect,  but  eventually  even  maximal  doses  failed  to  have 
demonstrable  effect  on  trypanosomes.  This  strain  on  passage  through 
another  animal  of  the  same  species  remained  resistant  for  many  genera- 
tions. This  phenomenon  Ehrlich  called  "  Festigkeit."  It  was  this 
resistance  which  particularly  interested  him,  and  caused  him  to  continue 
his  work  with  trypanosomes,  and  it  was  the  study  of  drug  resistance 
which  led  to  the  fundamental  conception  of  chemotherapy  responsible 
ultimately  for  the  introduction  of  "  606."  This  tolerance  on  the  part  of 
trypanosomes  holds  only  for  the  particular  type  of  remedy  used,  arsenic, 
antimony,  or  dye  substance,  but  once  firmly  established,  it  holds  for  other 
members  of  the  same  group.  Thus,  a  strain  which  is  resistant  to  fuchsin 
is  also  immune  to  the  related  basic  dyes,  but  not  against  azo  dyes,  arseni- 
cals, or  antimonials.  Similarly,  a  strain  resistant  to  arsacetin  is  also 
resistant  to  atoxyl.  The  resistance  to  atoxyl  is  easiest  obtained,  next, 
to  arsenophenylglycin,  and  finally  to  tartar  emetic. 

In  relation  to  arsenic  resistance,  a  peculiar  phenomenon  is  observed. 
A  strain  may  be  made  resistant  to  atoxyl,  without  being  resistant  to 
arsenious  acid,  arsenophenylglycin  or  antimony.  In  the  attempt  to  make 
this  strain  resistant  to  arsenious  acid,  resistance  to  antimony,  or  better 
to  tartar  emetic,  develops.  Another  striking  peculiarity  is  the  develop- 
ment of  a  temporary  resistance  to  tartar  emetic  in  producing  an  arsacetin 
fast  strain  without  developing  resistance  to  arsenious  acid.  Apparently 
resistance  to  arsenious  acid  is  accomplished  by  resistance  to  most  arsenical 
derivatives.  According  to  Ehrlich's  conception,  the  trypanosome  has 
many  chemoceptors.  In  relation  to  arsenic  and  its  acetyl  derivatives, 
there  exists  at  least  two.  The  formation  of  one  (the  arsenoceptor)  by 
atoxyl  does  not  interfere  with  the  acetylceptor  which  can  be  brought  into 
play  in  relation  to  arsacetin. 

It  is  difficult  to  see  why  it  is  easier  to  obtain  resistance  to  tartar  emetic 
by  first  establishing  tolerance  for  atoxyl.  In  relation  to  resistance,  it  is 
interesting  to  note  that  with  the  antimonials  employed  by  Abel  and  the 
writer,  no  resistance  developed,  except  perhaps  in  relation  to  the  donkey. 
In  rats,  many  treatments  with  many  passages  did  not  result  in  the 
slightest  diminution  of  the  effect  of  the  antimonials  employed. 

The  Role  of  the  Host. — A  drug  resistant  race  produces  a  disease 


I 


FACTORS  OF  PROGRESS  IN  THERAPY  871 

similar  in  every  respect  to  that  of  the  non-resistant  race.  The  resistance 
itself  remains  the  same  through  many  generations  (thousands)  in  as 
many  as  100  passages  through  the  same  species.  Passage  through 
another  animal  usually  does  not  affect  the  resistance;  thus  a  strain, 
atoxyl  resistant  in  the  mouse,  remained  unchanged  in  46  subsequent 
passages  through  rats,  no  treatment  with  atoxyl  having  been  given  in  the 
meantime.  In  transfer  to  another  animal,  the  disease  runs  its  natural 
course  in  that  animal  and  the  strain  regains,  as  a  rule,  its  original  sen- 
sitiveness to  the  drug  in  question. 

In  working  with  the  donkey,  Brienl  and  Nierenstein  encountered 
resistance  to  atoxyl  which  persisted  in  transferring  the  strain  to  the  rat. 
In  our  work,  we  found  in  two  rats,  which  were  infected  from  blood  of 
the  donkey  under  treatment  with  antimony,  a  temporary  resistance  to 
antimony.  Unquestionably  the  resistance  to  the  drug  is  most  marked  in 
the  animal  in  which  the  resistance  is  established,  but  a  lesser  degree  of 
resistance  is  sometimes  encountered  in  passage  to  a  new  species.  Resist- 
ance is  a  property  of  the  strain  but  is  most  marked  in  the  species  in 
which  it  was  created. 

Naturally,  in  relation  to  arsenic  tolerance,  the  arsenic  eaters,  the 
mountaineers  of  Styria,  come  to  mind.  Whether  or  not  heredity  plays  a 
role  in  this  has  never  been  determined.  By  some  the  increased  tolerance 
is  ascribed  to  lessened  absorption,  by  others  to  increased  excretion.  That 
it  exerts  a  decreased  effect  on  the  gastrointestinal  mucosa  has,  however, 
been  definitely  determined. 

Specific  Chemotherapy  of  Spirilla 

Hata('*),  working  in  Ehrlich's  laboratories,  carried  on  work  on 
spirilla,  utilizing  the  same  drugs  that  Ehrlich  used  in  his  work  on  trypano- 
somes.'  His  investigations  dealt  with  the  spirilla  of  relapsing  fever,  of 
chicken  spirillosis,  and  of  syphilis. 

Spirilla  of  Relapsing  Fr^t-r.— The  effect  of  each  chemical  was  first 
studied  in  the  test  tube,  the  drug  dissolved  in  water  or  alcohol  being  added 
to  a  blood-containing  spirilla  mixture  diluted  with  physiological  salt  solu- 
tion or  isotonic  sugar  solution  to  a  constant  quantity.  Usually  a  dilu- 
tion of  the  blood  of  thirty-  to  forty-fold  was  attained.  The  motility  of 
the  spirillae  was  investigated  at  the  end  of  one  hour,  immotility  being 
interpreted  as  death. 

The  animal  experiments  were  carried  out  with  mice  and  rats  with  an 
attenuated  virus,  but  with  equal  infections  so  far  as  possible  in  all  cases ; 
i.e.  one  in  which  the  organism  could  be  found  in  the  blood  of  the  animal 
on  the  following  day  and  in  about  equal  numbers,  this  necessitating  con- 


872     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

stantly  greater  dilution  for  the  same  quantity  injected,  since  virulence 
increases  with  constant  passage.  The  amount  of  blood  necessary  for 
this  varied  with  different  strains,  and  with  different  conditions.  Never- 
theless it  was  possible  to  obtain  a  fairly  constant  infection.  The  disease, 
as  its  name  indicates,  presents  frequent  relapses,  provided  the  animal  does 
not  die  in  the  first  attack.  Animals  were  grouped  in  series  according  to 
the  mortality  of  the  untreated  condition,  inasmuch  as  continuous  passage 
through  one  specifies  invariably  results  in  increased  virulence.  Chemicals 
were  administered  on  the  day  after  inoculations,  and  the  blood  studied 
microscopically  thereafter  for  a  period  of  60  days,  since  relapses  occur 
as  late  as  50  days. 

In  some  instances  test  tube  and  animal  experiments  give  similar 
results  but  not  invariably.  Obviously  the  animal  experiments  yield  the 
■truer  criterion  for  practical  results.  The  most  striking  results  were 
obtained  with  arsenicals.  The  three  arsenicals,  atoxyl,  arsacetin,  and 
arsenophenylglycin,  were  practically  inert  against  the  spirilla.  Arseno- 
phenol  was  itself  more  effective,  while  its  derivative,  dioxy  diamido- 
arseno-benzol,  both  as  acid  and  alkaline  salt  was  wonderfully  effective. 
The  effect  in  the  test  tube  is  but  slight,  solutions  of  1/10,000  being  neces- 
sary to  kill  the  spirilla.  Organisms  subjected  to  1/10,000  solution  of  the 
drug,  if  still  motile,  cause  the  disease  but  with  a  modified  course.  With 
dilution  of  1/100,000  the  disease  develops  immediately.  Permanent  cure, 
however,  could  be  effected  on  the  first  day  following  inoculation  by  doses 
well  below  the  danger  line. 

Hata  determined  the  toxicity  of  dioxy  diamido  arsenobenzol  for 
various  animals  with  the  following  result : 


Animal 

Application 

Dose  tolerated 

Mouse 

subcutaneously 
intravenously 

I  :  300  per  20  gms. 
I  :  300     "     20     " 

Rat 

subcutaneously 

0.2  gram  per  kg. 

Hen 

intramuscularly 
intravenously 

0.25    "         "      " 
0.08    "         "      " 

Rabbit 
I  c.c.  of  1/300  soln. 

subcutaneously 
intravenously 

0.1      "         "      " 
0.15    "         "     " 

Animals  vary  somewhat  in  susceptibility  to  both  the  disease  and  the 
drug.  But  by  taking  a  series  of  animals  it  is  possible  to  arrive  at  a  fair 
average  in  relation  to  both.  The  important  desideratum  to  determine  is 
the  relation  of  the  curative  dose  to  the  dose  tolerated.  Thus  for  mice 
Hata  found  the  following  in  relation  to  permanent  cure  : 


FACTORS  OF  PROGRESS  IN  THERAPY 


873 


Dose 

One  Trealinenl 

Two  Treatments 

Three  Treatments 

1 :6oo 

100  per  cent. 

1 :  700 
1 :8oo 

100  " 
100  "   " 

1 :  1000 
1 :  1500 
1 :  2000 

75  "   " 
18  "   " 
16  "   " 

100  per  cent. 

75  "   " 
66  "   " 

100  per  cent. 

100  " 

1 :  3000 

0  "   " 

0  " 

iZ      "   " 

This  result  is  important  as  indicating  the  increase  in  effectiveness  in 
repetition  of  the  treatment.  Better  results  were  not  obtained  with  more 
than  three  treatments. 

The  dose  curative  as  related  to  the  dose  tolerated  was  represented  by 

(  -  ).     The  following  results  were  obtained  with  single  and  repeated 
injections : 

With  single  injections,  300/800  or  1/2.7 

With  two  injections,  300/1000  or  1/3.3 

With  three  injections,  300/1500-2000  or  1/5  to  1/7. 


He  also  found  that  double  the  curative  dose  did  not  entirely  protect 
animals  which  were  inoculated  24  hours  subsequently,  although  the  course 
of  the  disease  was  modified.  Rats,  he  found,  tolerated  relatively  large 
doses,  and  the  ^  was  more  constant  (0.06  to  0.08  gms.  per  kg.),  com- 
pletely sterilized  and  was  well  tolerated  in  all  instances. 

As  the  result  of  his  work  it  was  evident  that  relapsing  fever  in  mice 
and  rats  could  be  readily  cured  by  single  doses  of  these  arsenicals,  with- 
out untoward  effects  of  any  kind. 

Experiments  with  Spirillosis  of  Fowls. — Spirillosis  of  chickens  is 
easily  cured  by  arsenicals.  Uhlenhuth  and  Gross  demonstrated  the  effec- 
tiveness of  atoxyl,  and  Uhlenhuth  and  Manteufel  that  of  atoxyl  acid 
mercury.  The  blood  of  canaries  on  the  third  day  was  diluted  15  to  20 
times  with  salt  solution  so  that  it  showed  about  20  spirilla  to  the  field, 
and  of  this  mixture  0.5  c.c.  was  injected  intramuscularly.  In  Hata's 
work,  treatment  started  on  the  second  day,  at  which  time  the  blood  was 
but  lightly  infected.  Untreated  animals  showed  a  mortality  of  thirty- 
three  per  cent.  The  drugs  tested  were  injected  into  the  pectoral  muscles, 
and  the  blood  of  the  animal  was  examined  subsequently  at  frequent  in- 
tervals. Many  arsenicals  gave  good  results,  the  best,  however,  being 
obtained  with  diamino-dioxy-arsenobenzol.  A  curative  dose  afforded 
considerable  immunity.  The  relative  value  of  various  arsenicals  is  indi- 
cated in  the  following  table  compiled  by  Hata : 


003 
o.o6 

f=H 

0.03 

1/3-3 

0.1 

0.  i  2/0.4 

0.04/0.1 

0.0035/0.2 

1/3-3 
1/2.5 
1/58 

0.0015/0.03 

1/20 

874     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

Atoxyl 

Arsacetin 

Arsenophenylglycin 
Arsenylic  acid   Hg. 
Dioxydiamido  arsenobenzol 
Amido  phenol  arsenoxyd 

Specific  Chemotherapy  of  Spirochetes  (Syphilis) 

The  brilliant  success  attending  the  use  of  arsenicals  in  experimental 
trypanosomiasis  and  spirillosis  attracted  to  them  widespread  attention 
which  resulted  in  their  being  tried  in  syphilis.  Atoxyl  was  studied  in 
relation  to  syphilis  in  apes  by  Metchnikoff  (-^),  Salmon,  and  Uhlenhuth 
and  his  collaborators,  and  in  syphilitic  keratitis  of  rabbits  by  Uhlen- 
huth (-*')  and  Levaditi  ('").  The  results  were  most  encouraging.  In  the 
meantime  clinical  studies  with  atoxyl  were  started  at  the  suggestion  of 
Salmon,  by  Lesser  (^^),  Lasser,  Qwanga,  and  von  Zeissl,  all  reports  indi- 
cating that  its  effect  was  considerable.  Other  arsenicals  were  tried, 
arsacetin  by  Neisser  {~^),  arsenophenylglycin  by  Alt,  and  cacodylates  by 
Murphy  in  this  country. 

Ehrlich  and  Rata  applied  themselves  to  the  investigation  of  syphilis, 
using  the  same  methods  which  had  proved  so  successful  in  their  other 
chemotherapeutic  studies.  The  work  was  carried  out  on  rabbits  in  which 
two  forms  of  syphilitic  diseases  can  be  produced,  namely,  keratitis  and 
syphilis  of  the  scrotum.  The  efficacy  of  the  treatment  was  determined 
by  noting  the  effects  on  the  lesions,  and  was  further  controlled  through 
Wassermann  studies. 

Syphilis  of  the  scrotum  was  first  produced  in  rabbits  by  Osiola  and 
later  by  Truffi  (^^).  A  fragment  of  cornea  from  experimental  luetic 
keratitis  is  transplanted  under  the  skin  of  the  scrotum.  In  approximately 
two  weeks  a  small  patch  of  infiltration  appears  which  increases  in  size  to 
that  of  a  bean,  then  breaks  down,  becomes  encrusted,  ulcerates,  and  pre- 
sents an  infiltrated  raised  margin.  In  the  untreated  animal,  the  chancre 
persists  for  as  long  as  four  or  five  months  at  times,  but  it  is  difficult 
to  obtain  a  uniform  disease  such  as  one  obtains  in  trypanosomiasis.  The 
Wassermann  becomes  positive  and  remains  so.  The  condition  is  one 
admirably  adapted  to  chemotherapeutic  studies,  the  Wassermann 
reaction,  provided  care  is  exercised  in  the  selection  of  the  inoculated 
animals,  furnishing  an  excellent  and  reliable  means  of  control  for  the 
general  condition,  while  the  local  lesion,  the  chancre,  lends  itself  to 
ordinary  clinical  investigations  and  to  the  determination  of  the  presence 
or  absence  of  treponema. 


FACTORS  OF  PROGRESS  IN  THERAPY  875 

Selected  infected  animals  were  subjected  to  intravenous  treatment 
in  varying  dosage  with  the  different  arsenicals.  With  diamido  dioxy- 
arsenobenzol,  Hata  found  that  "  the  spirilla  can  be  destroyed  absolutely 
and  i)iinicdiately  by  a  single  injection/'  and  that  "  no  relapses  occur/'  and 
that  the  local  lesion  subsequently  dries  up  rapidly  and  disappears.  This 
solved  from  an  experimental  viewpoint,  at  least,  the  treatment  of  syphilis. 
From  an  experimental  basis  the  "  therapia  sterilisans  magna"  was 
attained. 

The  Introduction  of  Salvarsan  into  Practice. — The  next  investigation 
concerned  the  clinical  value  of  salvarsan,  as  the  preparation  was  now 
called.  Ehrlich  determined  to  subject  it  to  critical  tests  to  prove  or  dis- 
prove its  value  before  introducing  it  into  general  use.  He  says,  "  many 
thousands  of  patients  must  be  treated  before  the  preparation  should  be 
available  for  general  introduction.  For  even  if  a  preparation  has  been 
tested  in  the  most  careful  way  by  means  of  experiments  on  animals  and 
has  been  recognized  as  good,  this  naturally  does  not  prove  that  it  is  also 
applicable  for  human  beings."  Idiosyncrasy  to  drugs  plays  considerable 
role  in  relation  to  human  therapy,  but  is  apparently  a  negligible  factor 
in  animals.  Salvarsan  was  therefore  subjected  to  crucial  tests  in  some 
of  the  leading  clinics,  its  value  established  and  its  dangers  ascertained 
prior  to  its  being  offered  to  the  profession. 

Special  commendation  must  be  accorded  Ehrlich,  not  only  for  his 
brilliant  work  in  chemotherapy,  but  also  for  the  sound  clinical  judgment 
exhibited  in  the  method  adopted  in  introducing  salvarsan  into  practice. 
It  was  first  used  in  selected  cases  in  the  best  clinics,  under  the  closest 
supervision,  its  effects  being  carefully  followed.  Later  it  was  used  in 
types  showing  complications,  and  its  contraindications  and  untoward 
manifestations  determined.  Eventually  satisfactory  methods  of  adminis- 
tration and  dosage  were  determined  so  that,  on  coming  into  general  use, 
excellent  results  were  obtained  from  the  first,  and  accidents  were 
extremely  mfrequent. 

These  studies  have  the  greatest  significance  in  medicine.  They  have 
not  only  yielded  efficacious  specific  treatment  for  syphilis,  relapsing  fever, 
and  sleeping  sickness,  but  have  revealed  the  possibilities  of  actually  creat- 
ing specifics  for  disease,  and  have  demonstrated  beyond  question  the 
advisability  of  determining  further  the  relation  of  pharmacological  action 
to  chemical  constitution. 

Specific  Chemotherapy  in  Protozoal  and  Bacterial  Diseases  Contrasted 

It  is  in  the  field  of  protozoan  infection  that  chemotherapy  has 
wrought    such    brilliant    results.      The    plasmodium    of    malaria,    the 


876     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

trypanosome  of  sleeping  sickness,  the  treponema  of  syphilis,  the  spirilla 
of  relapsing  fever  and  of  chicken  spirillosis,  all  yield  to  specifics.  But 
in  infectious  diseases  only  a  beginning  has  been  made,  there  being  but 
one  or  two  drugs  in  the  entire  pharmacopeia  which  may  be  said  to  exer- 
cise a  specific  effect  on  infectious  diseases.     (Vide  infra.) 

The  explanation  for  the  relative  failure  of  drugs  in  infectious  dis- 
eases is  not  apparent.  Syphilis  offers  the  best  opportunity  of  revealing 
the  secret  as  it  is  so  closely  allied  to  infectious  diseases.  For  many 
years  syphilis  was  considered  an  infectious  disease  due  to  Lustgarten's 
bacillus.  The  lesion  produced  is  an  infectious  granuloma  similar  to  that 
seen  in  tuberculosis  and  leprosy.  Not  until  1905  was  the  spirocheta  pal- 
lidum discovered  as  its  cause,  by  Schaudinn  and  Hoffmann. 

Later  this  organism  was  reclassified  and  named  treponema  pallidum. 
The  treponema  are  very  closely  related  to  spirilla  which  in  turn  are  closely 
related  to  bacteria. 

It  is  difficult  to  determine  where  protozoa  end  and  where  bacteria 
begin.  The  animal  and  vegetable  kingdom  merge  in  such  a  way  that 
doubt  often  arises  as  to  which  is  concerned.  Reliable  criteria  are  want- 
ing. A  comparative  study  of  the  borderline  infections  is  of  the  greatest 
importance. 

Immunity  reactions  interest  the  bacteriologist  and  serologist.  The 
work  on  trypanosomes  furnished  the  laws  of  chemotherapy  which  even- 
tually lead  to  a  cure  for  syphilis.  The  treponema,  which  is  surpassed  in 
versatility  only  by  the  B.  typhosis,  has  already  been  brought  under 
control.  The  writer  is  sanguine  enough  to  expect  similar  results  in 
infectious  diseases  when  the  combination  of  genius,  perseverance,  chem- 
istry, biology,  and  organizing  capacity  of  an  Ehrlich  is  brought  to  bear 
on  the  problem. 

(5)    Infection  and  Antiseptics 

The  discovery  by  Pasteur  of  microorganisms  as  the  cause  of  disease 
has  revolutionized  many  of  the  principles  and  much  of  the  practice  of 
therapy.  Immunotherapy,  however,  is  sharply  defined  from  pharma- 
cology. It  deals,  at  present,  largely  with  infection  and  with  specific 
immunity  reactions.  These,  undoubtedly,  are  physiochemical  in  origin, 
but  from  this  point  of  view  are,  as  yet,  but  little  understood.  Because  of 
the  definite  line  of  cleavage,  immunity  treatment  will  not  be  discussed 
here. 

Pharmacology  deals  with  l^acteria  borne  diseases  at  but  a  few  points, 
the  more  important  being:  (i)  in  the  treatment  of  pneumonia";  (2)  in 
the  treatment  of  rheumatism;   (3)   in  the  treatment  of  diseases  of  the 


FACTORS  OF  PROGRESS  IN  THERAPY  877 

genito-urinary  tract;  and  (4)  in  antiseptic  surgery,  particularly  in  the 
use  of  the  Carrel-Dakin  treatment. 

(  j)  Pneumonia. — Morgenroth  and  Halberstaedter  demonstrated  the 
efficacy  of  ethyhydroxy  cuprein  against  the  pneumococcus.  In  experi- 
mental pneumonia  its  effect  is  little  short  of  specific  and  much  greater 
than  that  of  quinine.  All  strains  of  pneumococci  are  inhibited  by  it  in 
vitro  in  dilution  of  1/100,000.  Some  promising  results  have  been 
secured  in  practice,  but  its  application  is  limited  owing  to  a  tendency  to 
produce  blindness  and  on  the  whole  its  use  so  far  has  not  been  satis- 
factory. 

(2)  Rhcimiatism. — Much  discussion  has  centered  about  the  question 
of  "  specificity  of  action "  of  salicylates  in  rheumatism.  Salicylates 
unquestionably  lower  the  fever  and  remove  the  pain  in  the  majority  of 
cases  of  acute  rheumatic  fever.  On  the  other  hand,  the  incidence  of 
endocarditis  is  not  diminished.  On  the  latter  account,  it  has  been  argued 
that  salicylates  have  no  specific  action,  but  so  far  as  their  effect  on  fever 
and  pain  is  concerned  they  have  a  definite  action  and  in  many  instances 
they  shorten  the  course  of  the  attack 

(j)  Diseases  of  the  Genito-urinary  Tract. — Certain  chemicals  mani- 
fest antiseptic  action  against  local  infection  in  the  body.  Thus  hexa- 
methylamine  in  acid  urine  unquestionably  affects  the  colon  bacillus  and 
exerts  a  curative  action  in  pyelitis  and  cystitis.  Other  chemicals,  notably 
argyrol,  protargol,  and  certain  dyes  influence  the  course  of  gonorrhea. 
These,  however,  do  not  belong  in  the  same  category  with  salvarsan  and 
syphilis. 

{4)  Antiseptic  Surgery. — Following  the  work  of  Pasteur  and  the 
adoption  of  the  germ  theory,  Lister  applied  antiseptic  principles  to  sur- 
gery. Aseptic  surgery,  in  reality  a  form  of  preventive  medicine,  proved 
so  effective  that  upon  it  was  laid  the  greater  stress,  antisepsis  in  conse- 
quence not  receiving  the  attention  it  actually  merited. 

But  with  the  advent  of  war,  came  the  need  for  antiseptic  surgery. 
For  reasons  quite  obvious,  asepsis  was  inapplicable.  Lister's  doctrine 
and  methods  were  tried,  but  with  disappointing  results,  which  at  first 
were  ascribed  to  technical  inadequacies,  but  later  to  incorrect  principles. 
In  fact,  eminent  authorities  insisted  that  sterilization  of  war  wounds  was 
impossible,  and  that  "  the  treatment  of  suppurating  wounds  by  means  of 
antiseptics  is  illusory,  an.d  that  belief  in  its  efficacy  is  founded  upon  false 
reasoning."  Lister's  clinical  observations  and  experiences  were  for- 
gotten, replaced  by  theories  and  experiments  in  vitro,  which  failed  to 
approach  the  actual  conditions  confronted. 

The  problem  was  attacked  by  Carrel  (^')  and  Dakin  (^')  on  simple 
and  logical  grounds,  to  wit,  the  utilization  of  a  substance,  non-irritating 


878     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

to  the  tissues  and  of  sufficient  bactericidal  power  to  kill  all  microbes  of  all 
varieties  present  in  the  wound,  for  in  the  beginning  at  least,  surgical 
infection  is  local  in  character.  Dakin  set  about  finding  such  a  substance, 
and  Carrel  devoted  himself  to  finding  the  most  effective  manner  of 
applying  it. 

The  problem  was  chemotherapeutic  in  nature.  Methods  such  as  were 
employed  by  Ehrlich  were  adopted.  Various  antiseptics  were  tried  until 
the  most  desirable  were  determined,  and  these  were  then  modified  to  best 
meet  the  conditions. 

The  Chemotherapy  of  the  Newer  Antiseptics 

The  germicidal  action  of  free  chlorine  and  the  hypochlorites  is  well 
known.  In  medicine  this  action  has  been  obtained  through  the  use  of 
chlorine  water,  chlorinated  lime,  Labarraque's  solution  (solution  of 
chlorinated  soda)  and  Javelle  water  (solution  of  chlorinated  potash). 

Hypochlorite  solutions  are  relatively  permanent,  provided  they  are 
alkaline,  but  the  degree  of  alkalinity  encountered  in  Labarraque's  solu- 
tion, for  instance,  is  destructive  to  the  tissues  and  skin  as  well  as  to 
bacteria.  The  problem  chemically  consisted  of  retaining  the  bactericidal, 
while  deleting  or  minimizing  the  tissue-destroying  properties  of  the 
preparation. 

Tissue  destruction  was  found  to  be  dependent  to  a  large  extent  on  the 
alkalinity.  Therefore,  the  usual  solution  of  chlorinated  soda,  made  from 
chlorinated  lime  and  monohydrated  sodium  carbonate,  was  neutralized 
with  boric  acid  to  the  degree  of  alkalinity  determined  by  experiment  to 
be  least  irritating  to  the  tissues.  This  was  found  to  be  at  a  point  where, 
on  adding  powdered  phenolphthalein,  no  color  reaction  occurred,  while 
the  addition  of  one  per  cent,  alcoholic  phenolphthalein  solution  still 
resulted  in  a  red  flash,  the  color  quickly  fading.  Such  a  solution  can  be 
used  without  marked  irritation  to  well  vascularized  tissues.  The  skin, 
however,  proves  an  exception  which  necessitates  the  use  of  petrolatum  as 
a  protective  agent. 

Raschig  had  already  shown  that  the  addition  of  ammonia  to  hypo- 
chlorite solution  resulted  in  the  formation  of  chloramines.  Dakin 
ascribed  the  antiseptic  power  of  resulting  compounds  to  the  NCI  group- 
ing, since,  "  The  parent  substances  from  which  these  chloramines  are 
prepared,  whether  substituted  or  containing  chlorine  attached  to  carbon, 
show  no  such  action."  A  series  of  substances  containing  the  NCI  group- 
ing with  sulphur,  benzine,  naphthalene,  and  other  radicles  were  investi- 
gated with  the  following  important  conclusions : 

"  ( I )  Almost  all  the  substances  examined  containing  the  NCI  group 
possess  very  strong  germicidal  action. 


FACTORS  OF  PROGRESS  IN  THERAPY  879 

"  (2)  The  presence  in  the  molecule  of  more  than  one  NCI  group 
does  not  confer  any  marked  increase  in  germicidal  power. 

"  (3)  The  germicidal  action  of  many  chloramine  compounds  is, 
molecule  for  molecule,  greater  than  that  of  sodium  hypochlorite. 

"  (4)  The  chloramine  derivatives  of  naphthaline  and  other  di-cyclic 
compounds  of  the  sulphochloramide  type  closely  resemble  the  sulphur 
aromatic  chloramines  in  germicidal  action. 

"  (5)    Bromamines  are  less  effective  as  germicides. 

"  (6)  Derivatives  of  proteins  prepared  by  the  action  of  sodium  hypo- 
chlorite and  containing  NCI  groups  are  strongly  germicidal.  Blood 
serum  inhibits  their  germicidal  action  to  much  the  same  extent  as  it  does 
with  sodium  hypochlorites  and  the  aromatic  chloramines." 

Mode  of  Action  of  Hypochlorites. — Dakin  has  duly  considered  the 
mode  of  action  of  hypochlorites,  and  offers  the  following  explanation. 
When  the  hypochlorite  solution  comes  into  contact  with  protein,  a  reaction 
occurs  analogous  to  the  interaction  between  ammonia  and  hypochlorites, 
resulting  in  the  formation  of  chloramines : 

H2NH  +  NaClO  =  H2NCI  +  NaOH 

The  bactericidal  effect  is  chemical  in  nature,  due  to  such  a  reaction 
occurring  in  the  protein  of  the  organism  itself,  or  in  the  medium  in  which 
the  organism  is  suspended,  in  either  instance  the  resulting  chloramine 
being  responsible  for  the  death  of  the  microbe.  In  this  reaction,  CI  is 
substituted  for  the  H  of  the  amino  group  (NH2),  the  CI  uniting 
directly  to  the  N,  with  the  formation  of  chloramine.  In  other  words,  the 
capacity  of  hypochlorites  to  attack  proteins  and  to  form  compounds  with 
them  in  which  the  halogen  is  directly  attached  to  the  nitrogen  is 
responsible  for  their  bactericidal  effect. 

The  destructive  action  of  hypochlorites  on  skin  and  tissue  is  asso- 
ciated with  their  soda  content.  Their  action  on  living  tissues,  according 
to  Guillaumir  and  Vienne,  is  modified  by  the  concentration  present  of 
other  salts,  a  process  known  to  the  tanners  as  "  pickling."  Dakin  cor- 
rected the  excess  alkalinity,  but  whatever  the  explanation,  the  fact 
remains  that  living  tissues  evidence  marked  resistance  to  the  destructive 
action  of  Dakin's  solution. 

Mode  of  Action  of  Chloramines. — Chloramines  kill  organisms  more 
readily  or  at  a  lower  molecular  concentration  than  corresponding  hypo- 
chlorites, from  which  it  may  be  argued  that  the  compound  as  a  whole 
exercises  some  toxicity.  They  react  with  amino-acids,  peptones,  and  pro- 
teins in  the  same  way  as  hypochlorites,  thus  chloramine  T.  (p.  toluene 
sodium  sulphochloramid)  reacts  with  glycin  in  the  following  manner: 

CHsCcH^SO.Na:  NCI  +  CH.(NH.)COOH  =  CH.(NHCl)COONa  +  CH3C6H4SO2NH, 
CH2(NHCl)COONa  +  H.O  =  H=CO  +  CO.  +  NaCl  +  NH. 


88o      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 


Peptones  and  proteins  probably  react  in  a  manner  similar  to  amino- 
acids,  biU  more  slowly.  It  appears  that  chloramines  can  act  as  chlorin- 
ating agents  upon  important  constituents  of  living  cells,  and  this  may 
play  an  important  role  in  their  antiseptic  properties. 

As  a  result  of  these  facts,  Dakin  drew  the  following  tentative  con- 
clusions : 

(i)  The  fact  that  proteins  contain  N  in  a  form  capable  of  attracting 
CI  from  chloramines,  is  probably  a  factor  in  the  germicidal  action  of 
chloramines. 

(2)  The  superior  germicidal  action  of  chloramines  over  hypo- 
chlorites is  due  to  special  toxic  action  of  the  chloramine  molecules,  or 
"  possibly,  to  selective  chlorination  of  particular  cell  constituents." 

Carrel's  problem  cannot  be  better  summed  up  than  has  been  done  by 
himself.  Speaking  of  his  method,  he  says,  "  The  method,  therefore,  is 
based  upon  the  employment,  rigorously  controlled  by  the  microscope,  of 
an  approved  agent,  under  conditions  of  contact,  of  concentration,  and 
of  duration,  established  by  direct  experiment  upon  infected  wounds." 

In  order  to  determine  its  effectiveness,  an  antiseptic  must  be  con- 
sidered from  the  following  points  of  view  :  "  its  capacity  of  irritating 
tissues,  its  toxicity,  its  solubility,  its  power  of  penetrating  the  tissues,  and 
of  being  absorbed  by  them,  and  the  manner  in  which  it  reacts  with 
product  and  other  constituents  of  the  tissues." 

Each  of  these  factors  received  special  consideration  and  was  made  the 
subject  of  experimentation.  Because  of  their  important  role  in  the  action 
of  antiseptics,  proteins  were  considered  in  all  their  work,  microorganisms 
being  suspended  in  blood  serum  instead  of  water  while  determining  the 
antiseptic  properties  of  drugs.  The  importance  of  this  is  indicated  in  the 
following  table  compiled  by  Carrel  and  Dehelly  from  experiments  of 
Dufresnes  on  the  action  of  antiseptics  on  bacteria. 


Antiseptics 

Without  blood-sernm 

With  blood-serum 

Acid  carbolic 

1 :  250  — 

1:50  — 

"            " 

1:500  + 

1 :  100  + 

Acid  salicylic 

1 :  2500  — 

1 :  100  — 

It                       u 

1 :  5,000  + 

1 :  250  + 

Hydrogen  peroxide 

1 :  3,500  — 

1 :  1,700  — 

"                 " 

I  :  8,000  -f- 

1 :  2,000  -}- 

Iodine                " 

I  :  ioo,coo  — 

I  :  1,000  — 

"                     " 

1 :  10,000,000  + 

1 : 2,500  + 

Bichloride  of  mercury 

I  :  5,000,000  — 

1 :  25,000  — 

"            "         " 

1 :  10,000,000  + 

1 :  50,000  + 

Nitrate  of  silver 

I  :  1 ,000,000  — 

I  :  10,000  — 

<(        ((       (1 

I  :  10,000,000  + 

1 :  25,000  + 

Hypochlorite  of  soda 

I  :  500,000  — 

i:  1,500  — 

11              <i       11 

T  :  T  ,000,000  -f 

1 :  2,000  + 

The  sign  (  +  )  indicates  that  the  culture  is  positive,  and  the  sign  (- 
sterile. 


-)  that  it  remained 


FACTORS  OF  PROGRESS  IN  THERAPY  88i 

The  power  of  penetration  was  determined  by  immersion  in  antiseptic 
solution  of  small  blocks  of  infected  tissues,  followed  by  incubation  and 
subsequent  cultures.  In  this  manner  it  was  found  that  hydrogen  per- 
oxide, for  instance,  failed  to  sterilize  blocks  of  infected  liver  when  cubes 
larger  than  one  millimeter  were  employed,  B.  welchii  being  the  infecting 
organism. 

The  effect  on  tissues  was  ascertained  in  the  following  manner : 
Dakin's  solution,  Eau  de  Javel,  and  Labarraque's  solution,  all  of  equal 
strengths  (0.5%),  were  placed  in  containers.  To  each  was  added  a  frag- 
ment of  skin  from  a  stillborn  babe.  At  the  end  of  two  hours,  the  frag- 
ments in  Javel's  and  Labarraque's  solutions  were  greatly  swollen,  and 
the  epidermis  readily  detachable;  subsequently  they  became  transparent, 
and  in  ten  to  twelve  hours  were  completely  dissociated.  The  tissue  in 
the  Dakin's  solution  after  twenty-four  hours  was  in  a  condition  similar 
to  that  existing  in  the  other  solutions  after  two  hours. 

The  antiseptic  solutions  were  next  studied  in  infected  wounds  them- 
selves. "  When  hypochlorite  of  soda  is  applied  to  a  wound  in  such  a 
manner  that  its  degree  of  concentration  remains  constant,  and  the  dura- 
tion of  the  application  is  prolonged,  the  microbes  disappear."  It  was 
determined  that  this  result  was  not  due  to  spontaneous  sterilization,  to 
mechanical  washing  away  by  the  instilled  liquid,  or  to  alkalinity  of  the 
solutions.  Toxicity  was  determined  by  subcutaneous  and  intravenous 
injections  into  animals. 

The  action  of  the  antiseptics  on  living  wounded  and  healthy  tissue 
was  next  investigated.  "  Dakin's  solution  possesses  a  concentration 
which  allows  one  to  make  use  of  the  differences  of  resistance  presented 
on  the  one  hand  by  microbes,  free  anatomical  elements  and  necrosed 
tissue,  and  on  the  other  hand,  normal  tissue  equipped  with  a  circulation. 
It  destroys  the  first  and  does  not  damage  the  second."  The  factors  con- 
sidered in  their  work  in  this  connection  were  the  condition  of  the  wound, 
the  measurement  of  wounds,  the  cicatrization  of  infected  wounds,  and 
the  cicatrization  of  aseptic  wounds,  the  influence  of  the  drug  being  deter- 
mined in  each  instance. 

The  following  preparations,  after  intensive  study  in  war  surgery, 
have  proved  of  value  as  local  antiseptics :  surgical  solution  of  chlorinated 
soda  (Carrel-Dakin),  chloramine  T.,  and  dichloramine  T. 

The  Carrel-Dakin  solution  in  concentrations  up  to  0.4  or  0.5  per 
cent,  is  applied  by  practically  continuous  irrigation  according  to  methods 
developed  by  Carrel  which,  however,  are  too  technical  to  be  discussed  in 
this  connection.  Chloramine  T.  sodium  paratoluenesulphochloramide,  in 
one-half  per  cent,  aqueous  solution,  is  used  in  the  same  way.  It  has  the 
advantage  of  greater  solubility,  convenience  of  preparation,  and  less  local 


882      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

irritation,  but  lacks  the  solvent  action  of  the  hypochlorites.  It  can  be  pre- 
pared up  to  eight  per  cent,  by  solution  in  chlorcosone  or  chlorinated 
paraffin  oil.  Dichloramine  T.,  or  paratoluenesulphondichloramide,  is 
but  slightly  soluble  in  water  and  hence  is  used  exclusively  in  oil  (chlo- 
rinated eucalyptus  oil  or  chlorcosone).  It  is  more  irritant  and  also  more 
solvent  than  chloramine  T. 

Surgical  Experience  with  These  Antiseptics 

Abundant  proof  has  accrued  as  to  the  value  of  these  newer  anti- 
septics. Opposed  by  some,  enthusiastically  received  by  others,  they  have 
been  "  weighed  in  the  balance  "  in  war  surgery,  and  have  not  been 
"  found  wanting."  Like  all  other  remedies,  they  have  their  indications 
and  contraindications. 

In  all  cases,  general  surgical  principles  should  first  be  applied.  In 
fact,  some  surgeons  still  believe  that  the  debrisement  operation,  mechani- 
cal cleansing,  and  physiological  rest,  are  all  that  are  necessary.  But  of 
those  who  have  tried  debrisement  alone,  and  Carrel-Dakin's  treatment 
alone,  and  the  combination  of  the  two,  the  majority  recognize  great 
virtues  in  these  antiseptics.* 

The  chief  value  of  these  antiseptics  is  found  in  the  treatment  of 
infected  wounds  where  the  infection  is  near  the  wound  surface  or  super- 
ficial in  character.  The  exudate  present  appears  to  enhance  somewhat 
the  antiseptic  action,  and  to  prove  a  source  of  protection  against  tissue 
destruction  on  the  part  of  the  solution.  Thus  superficial  abcesses, 
infected  burns,  infected  abdominal  wall  wounds,  and  amputation  stumps 
where  suppuration  already  exists,  respond  particularly  well.  Sterilization 
of  the  ulcer  with  Dakin's  solution  immediately  increases  the  chances  for 
"  takes  "  in  skin  grafts. 

On  the  other  hand,  clinical  experience  has  proved  that  in  fresh  unin- 
fected wounds  and  in  the  presence  of  great  cicatrization  Dakin's  solution 
is  of  but  little  value  and  harmful  at  times.  In  the  former,  Dakin's  solu- 
tion results  in  the  destruction  of  tissues,  especially  to  those  poorly  vascu- 
larized, such  as  cartilage  and  tendons.  Nerves,  on  the  other  hand,  are 
but  little  affected.  In  deeply  infected,  markedly  cicatrized  or  stratified 
wounds,  the  treatment  usually  fails  utterly. 

In  applying  the  treatment,  certain  cardinal  considerations  must  be 
borne  in  mind;  namely,  contact  of  the  solution  with  every  part  of  the 
wound,  mechanical  cleansing  of  the  wound  with  the  removal  of  all 
foreign  bodies,  the  use  only  of  solutions  properly  prepared  and  of  proper 
strength,  and  finally,  absolute  adherence  to  the  technique  described  until 

*  These  statements  emanate  from  the  large  experience  of  my  surgical  colleague, 
Dr.  J.  F.  Corbctt,  who  has  utilized  these  antiseptics  extensively  in  war  surgery  and  in 
the  wards  of  the  university  hospital. 


FACTORS  OF  PROGRESS  IN  THERAPY  883 

such  time  as  experimental  and  clinical  proof  is  furnished  of  the  superi- 
ority of  modifications.  Only  by  strict  observance  of  these  directions 
can  the  best  results  be  obtained. 


(6)    The  Role  Played  by  Glands  of  Internal  Secretion 

Metabolism. — Eternal  as  the  everlasting  hills,  metabolism  goes  on, 
the  basis  of  life  and  all  its  phenomena.  While  "  men  may  come  and  men 
may  go,"  like  Tennyson's  brook,  it  goes  on  forever.  Species  are  cast  in 
various  molds,  generations  appear  and  disappear,  youth  is  followed  by 
age,  yet  through  it  all  running  along  on  predetermined  lines  goes 
metabolism.  Where  there  is  life  there  is  chemical  reaction,  and  regu- 
lating this  are  the  endocrine  glands,  the  glands  of  internal  secretion. 

Protoplasm  from  the  physician's  point  of  view  is  not  matter.  The 
cell  is  the  seat  of  vitality,  of  chemical  exchange,  of  growth,  of  function, 
and  of  life.  The  assimilation  of  nutriment,  growth,  reproduction  of 
kind,  inflammation,  degeneration,  regeneration,  exercise  of  function, 
motion  and  emotion  are  all  matters  of  chemistry.  Species,  genus,  and 
time  of  life  are  accidents  determined  by  heredity,  while  size,  weight,  and 
sometimes  appearance,  are  matters  of  metabolism,  which  in  the  individual 
is  controlled  by  the  internal  secretions  and  also  by  the  nervous  system. 

Physiological  alchemy  held  sway  for  centuries  and  introduced  many 
fundamental  ideas.  Exact  sciences,  physiology  and  physical  chemistry, 
are  rapidly  replacing  it,  bringing  light  into  darkness. 

The  basis  on  which  the  science  of  nutrition  rests  was  laid  in  1780  by 
Lavoisier.  Lusk  (^^)  says  of  him,  "  He  was  the  first  to  apply  the  balance 
and  thermometer  to  the  investigation  of  the  phenomena  of  life,"  and  he 
declared,  "  La  vie  est  une  fonction  chimique."  He  established  the  true 
character  of  the  "  dephlogisticated  air "  of  Priestley,  and  through 
researches  on  animal  heat  and  on  respiration  established  the  relationship 
of  oxygen  to  bodily  functions.  He  quantitatively  determined  in  man  the 
oxygen  used  per  hour,  the  influence  of  temperature  on  the  quantity  used, 
the  relation  of  oxygen  to  digestion  and  to  exercise,  thus  establishing  the 
relation  of  oxygen  absorbed  and  CO2  excreted  to  food,  work,  and 
temperature. 

Liebig  (^*)  became  interested  in  nutrition,  and  studied  biology  along 
chemical  lines.  Voit,  inspired  by  his  work,  devoted  himself  to  problems 
of  nutrition,  but  particularly  to  the  role  played  by  nitrogen  in  protein 
metabolism.  He  calculated  the  nitrogen  content  of  food,  determined  its 
excretion  in  the  urine,  and  showed  the  relationship  of  urea  output  to 
nitrogen  intake.  He  suggested  to  Pettenkofifer  (^^)  the  need  of  an  appa- 
ratus by  which  the  total  carbon  excretion  might  be  measured,  a  problem 


884     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

which  they  undertook  jointly.  The  respiration  apparatus  was  completed 
in  1862.  Voit  next  "  computed  from  the  substances  oxidized  in  the  body 
the  quantity  of  heat  which  should  have  arisen  from  the  destruction  of 
these  substances."    Thus  was  established  indirect  calorimetry. 

Rubner  in  1894,  working  in  Voit's  laboratory,  made  accurate  deter- 
mination through  calorimetric  methods  of  the  heat  value  of  urea  and  of 
dry  urinary  solids,  through  which  were  established  biological  standards 
for  the  caloric  values  of  proteins,  carbohydrates,  and  fats.  In  1894  he 
built  the  first  successful  respiration  calorimeter  which  actually  measured 
heat  production  in  the  dog,  and  in  so  doing  established  direct  calorimetry. 

Atwater,  while  in  Germany,  was  associated  with  Voit  and  Rubner.  In 
1877  he  investigated  the  dietary  requirement.  In  1894,  through  the  assist- 
ance of  the  American  government,  he  and  Rosa  started  the  construction 
of  a  respiration  calorimeter  for  man,  which  was  completed  in  1897. 

Through  the  labors  of  Lusk,  Benedict,  and  Dubois  C""),  calorimetry 
has  been  made  applicable  to  clinical  medicine  and  practical  therapy.  Indi- 
rect calorimetry  is  coming  into  general  use  in  the  larger  clinics.  For  com- 
parative purposes  a  normal  control  is  always  essential.  This  for  clinical 
studies  is  found  in  the  rate  of  basal  metabolism,  which  is  expressed  in 
calories  per  hour  per  square  meter  of  body  surface.  The  variation  from 
the  normal  average  is  expressed  in  terms  of  percentage  above  and  below 
normal. 

In  this  manner  developed  the  science  of  nutrition,  whereby  is  revealed 
the  function,  value,  and  fate  of  food.  Through  gas  analysis,  determina- 
tions of  heat  production  and  analysis  of  excreta,  the  possibility  was 
revealed  of  determining  quantitatively  the  role  played  by  various  foods, 
such  as  proteins,  carbohydrates,  and  fats  in  metabolism  and  their  rela- 
tionship to  heat  and  energy  production,  to  growth,  and  to  the  processes 
of  building  up  and  repairing  of  tissues.  With  increase  in  the  knowledge 
of  metabolism,  of  physiological  chemistry,  and  of  medicine  in  general, 
the  relation  of  disturbances  of  metabolism  to  disease  became  manifest. 
Detailed  studies  of  these  disturbances  is  shedding  much  light  on  both 
the  processes  of  normal  metabolism  and  that  of  disease. 

In  metabolic  studies  attention  centered  in  the  mechanisms  involved  in 
digestion,  storage,  and  assimilation  of  foods,  in  their  fate  and  function 
under  varying  conditions,  and  in  the  factors  affecting  metabolic  processes 
generally,  such  as  oxidation,  cleavage,  deamidization,  reduction,  and 
synthesis. 

Nutrition  and  Food  Values 

In  the  space  allotted,  it  is  impossible  to  attempt  more  than  an  outline 
in  a  general  way  of  the  more  important  phases  of  nutrition,  the  role 


FACTORS  OF  PROGRESS  IN  THERAPY  885 

played  by  the  glands  of  internal  secretion,  and  the  use  of  glands  or  their 
products  in  organotherapy. 

Foods  are  utilized  by  the  body  as,  (a)  material  for  construction  of 
body  substance,  (b)  to  make  good  the  losses  incurred  in  the  wear  and  tear 
of  life,  i.e.  maintenance,  (c)  to  supply  energy  for  life's  activities,  and 
(d)  to  supply  heat.  The  foods  required  are  carbon,  hydrogen,  nitrogen, 
oxygen,  sulphur,  phosphorus,  chlorine,  iron,  salts,  and  water.  Some  of 
them  must  be  prepared,  since  higher  organisms  have  not  the  same  ca- 
pacity as  the  lower  of  building  up  their  own  food  from  simple  chemical 
compounds.  The  carbon  and  hydrogen  produce  energy  through  oxida- 
tion; nitrogen  is  utilized  for  repair  of  structures  containing  nitrogen,  and 
secondarily  for  energy;  oxygen  is  needed  for  oxidation  of  carbon  and 
hydrogen  and  is  the  chief  source  of  energy;  sulphur  is  necessary  for 
growth,  and  repair  of  structure  containing  sulphur;  phosphorus,  for 
growth  and  repair  of  structures  containing  phosphorus;  iron  for  hemo- 
globin; salts  for  osmotic  pressure;  and  water  for  facilitating  solution, 
and  for  carrying  off  waste  products  in  excretion.  The  nitrogen  and 
carbon  must  be  in  forms  as  complex  as  amino-acids  and  the  sugars 
respectively.  The  classes  of  foodstuffs  are  ordinarily  carbohydrates,  pro- 
teins, and  fats,  the  caloric  values  of  which  have  been  accurately  deter- 
mined. But  calories  do  not  always  suffice ;  these  may  be  supplied  in  abun- 
dant quantities  without  maintenance  or  growth. 

It  is  just  at  this  point  that  recent  advances  have  been  made.  In 
addition  to  caloric  values,  there  are  other  factors  known  as  accessory 
factors.  These  are  of  two  kinds:  (a)  originating  from  without,  bau- 
steine  and  vitamines,  (b)  arising  from  within,  hormones  or  internal 
secretions. 

Baiistcinc,  or  Building  Stones. — Proteins  from  different  sources  dift'er 
chemically  and  biologically.  Newer  knowledge  of  the  structure  of  these 
highly  complex  nitrogenous  compounds  makes  possible  a  new  conception 
of  protein  metabolism.  The  nitrogen  must  be  in  the  form  of  a  molecule 
at  least  as  complex  as  an  amino-acid  before  it  can  be  utilized  in  the  body. 
Such  units  constitute  building  stones,  or  "  bausteine."  The  work  of 
Osborne,  and  Mendel  C'),  and  of  McCollum  (^^)  in  this  country  and  of 
Abderhalden  (^^)  in  Germany  introduces  a  new  conception  of  nutrition 
and  also  a  broader  conception  of  the  function  of  the  cell  in  its  capacity  to 
synthesize. 

■  Proteins  are  broken  down  in  digestion  into  amino-acids.  These  are 
absorbed,  circulate  as  building  stones,  and  are  utilized  by  the  cell  in  the 
building  up  of  new  protein.  For  maintenance  certain  amino-acids  are 
necessary ;  for  growth,  still  others  are  needed.  In  so  far  as  a  protein  pos- 
sesses in  its  molecule  the  building  stone  needed,  just  so  far  can  it  be 


886      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

utilized  for  maintenance  or  growth.  For  example,  if  only  proteins 
deficient  in  cystin  (a  sulphur-containing  amino-acid)  are  furnished  the 
body,  the  production  of  new  cystin-containing  bodies  will  be  difficult  and 
limited  by  the  supply  in  the  food  ingested.  Through  feeding  artificial 
food  mixtures  to  mice  the  importance  of  certain  bausteine  have  been 
demonstrated,  tryptophane  for  maintenance  and  glycin  and  lysin  for 
growth.  For  maintenance  the  addition  of  tryptophane  is  necessary  to 
zein,  carbohydrate,  and  fat  diet  and  also  to  completely  hydrolyzed 
(enzymatic)  proteins.  For  growth  of  mice,  milk  must  be  added  to  mix- 
tures of  pure  caseinogen,  fats,  carbohydrates,  and  salts,  and  lysin  to 
certain  other  food  mixtures.  The  body  can,  however,  synthesize  gly- 
cocoll. 

Similar  requisites  probably  exist  in  the  field  of  lipoids.  Thus  cod 
liver  oil,  so  long  utilized  in  nutritional  diseases  of  childhood,  is  shown  to 
facilitate  growth  in  mice  in  artificial  food  mixtures  when  lard  fails. 
This  is  another  instance  of  sound  empiricism  which  is  now  being 
rationalized. 

Vitamines. — For  normal  metabolism  vitamines  are  necessary.  Little 
is  known  of  their  character  or  of  their  mechanism  of  action.  In  their 
absence  diseases  appear.  Reintroduced  to  the  diet  after  prolonged 
absence,  they  sometimes  result  in  cure.  Lack  of  fresh  vegetables  and 
fruit  juices  may  result  in  scurvy,  lack  of  rice  polishings  in  beriberi,  while 
absence  of  eggs,  meat,  and  milk  in  the  diet  is  responsible  for  pellagra. 
These  are  known  as  deficiency  diseases,  and  their  treatment  consists  of 
the  addition  of  appropriate  foods  to  the  dietary. 

Funk  (^°),  who  first  recognized  the  existence  and  importance  of 
vitamines,  has  attempted  their  isolation.  To  the  vitamine  of  rice  polish- 
ings, he  has  ascribed  the  formula  Cae  H;>o  O9  N4  and  believes  it  to  be  a 
tetrabasic  acid.  But  inasmuch  as  its  formula  closely  resembles  that  of 
nicotinic  acid  (*^)  (an  inert  substance  from  this  point  of  view)  further 
work  is  necessary.  Hopkins  (*")  feels  that  the  true  vitamine  is  still 
unknown.    It  belongs  to  the  "  water  soluble  A  "  class  of  McCollum. 

Hormones,  Internal  Secretion. — The  work  of  Starling  and  Bayliss  (") 
resulting  in  the  recognition  of  hormones  or  internal  secretions  opened  up 
a  new  chapter  of  physiology  and  revealed  the  existence  of  another  factor 
in  metabolism  which  is  of  the  greatest  importance  to  medicine.  The 
endocrine  glands  manufacture  substances  which  act  as  catalysts  and 
markedly  affect  metabolism.  Under-  or  over-production  of  them  results 
in  the  development  of  diseases  of  metabolism;  thus,  the  absence  of  thy- 
roxin leads  to  myxedema;  of  the  secretion  of  pancreas  (islets  of  Langer- 
hans)  to  diabetes;  of  tethelin  to  infantilism;  of  the  extract  of  the  pos- 
terior lobe  and  pars  intermedia  of  the  pituitary  to  diabetes  insipidus; 


FACTORS  OF  PROGRESS  IN  THERAPY  887 

of  the  parathyroids  to  tetany;  and  of  some  secretion  of  the  adrenals  to 
Addison's  disease.  On  the  other  hand,  excess  of  thyroxin  leads  to 
exophthalmic  goitre  and  of  tethelin  to  gigantism  or  acromegaly. 

These  secretions  are  chemical  entities,  one  of  them,  thyroxin,  having 
already  been  synthesized  and  used  therapeutically.  Future  therapy  will 
probably  use  synthetic  drugs  to  replace  these  internal  secretions  in  the 
diseases  of  metabolism  in  which  they  are  deficient. 

In  relation  to  metabolism,  attention  should  be  called  to  the  "  specific 
dynamic  action  of  protein."  In  studies  of  basal  metabolism,  it  has  been 
found  that  proteins  stimulate  the  rate  of  metabolism  more  than  carbo- 
hydrates. Some  of  the  amino-acids,  for  instance  glycin  and  alanin, 
exhibit  this  property.  It  is  supposed  to  be  due  to  the  direct  stimu- 
lating action  of  some  of  the  intermediary  acids  such  as  lactic  and 
peruvic. 

Little  is  known  concerning  the  effect  of  drugs  on  metabolism,  but 
since  the  synthesis  of  thyroxin  has  already  been  accomplished,  it  would 
appear  that  the  day  of  drug  control  of  metabolism  is  at  hand.  The 
influence  of  caffeine  and  strychnine  has  been  determined  by  Edsall  and 
Means  (*^)  and  Higgins  and  Means  (")  and  of  adrenalin  by  Sandiford. 
Opium  is  said  to  slow  the  rate  of  metabolism.  The  effects  of  these  drugs 
on  metabolism  are  in  all  probability  due  to  their  effects  on  the  neuro- 
muscular system,  whereby  acceleration  on  the  one  hand  and  inhibition  on 
the  other  occur.  Cacodylate  of  sodium  has  been  utilized  clinically  to 
control  the  increased  rate  of  metabolism  in  exophthalmic  goitre;  arsenic 
and  phosphorus  in  therapeutic  doses  are  both  said  to  check  oxidation  and 
to  favor  nutrition  in  growth. 

Growth 

A  new  science  of  growth  is  in  the  making.  Life  is  a  sequence; 
embryonic  life,  birth,  infancy,  childhood,  adolescence,  maturity,  and 
senility  follow  each  other  unless  death  intervenes.  Growth  characterizes 
the  young.  According  to  Lee,  it  consists  of  only  three  processes : 
multiplication  of  cells,  enlargement  of  cells,  and  deposition  of  intercel- 
lular substance.  Great  variations  from  the  mean  are  uncommon,  and 
until  recent  years  have  not  been  subject  to  explanation.  But  investiga- 
tion in  the  field  of  growth,  nutrition,  and  hormone  actions,  is  doing  much 
to  elucidate  this  subject. 

Growth  is  a  function  of  the  cell.  Two  or  perhaps  three  fundamental 
factors  are  concerned;  namely,  growth  impulse,  nutrition,  and  accessory 
factors  such  as  hormones  and  vitamines.  The  first  we  do  not  understand, 
it  is  life  itself.  Nutrition  is  controlled  by  laws  of  physiology,  of  chem- 
istry, and  physics.     The  importance  of  the  accessory   factors  are  just 


888      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

beginning  to  be  recognized.  Growth  is  regulated  for  each  species,  the 
same  food  in  the  same  amounts  fed  to  different  species  resulting  in  dif- 
ferent rates  of  growth. 

Metabolism  or  nutrition  in  the  young  organism  differs  in  some 
respects  from  that  of  adult  life.  Additional  processes  are  at  work 
involved  in  changes  in  character  of  tissue,  such  as  ossification  of  bone 
and  union  of  epiphyses.  But  the  chief  difference  lies  in  growth  or  the 
creation  of  new  tissues,  which  involves  the  building  up  of  new  proteins. 
The  ordinary  foodstufifs  play  the  same  role  as  in  adults.  Maintenance 
can  be  procured  in  mice  on  the  same  artificial  food  mixtures  utilized  in 
the  nutrition  experiments  for  growth,  but  the  bausteine,  tryptophane, 
glycin,  and  lysin  are  absolute  requisites  for  growth.  The  addition  of 
small  quantities  of  lactalbumen  and  of  edestin  to  zein,  fed  to  mice, 
increases  growth  out  of  all  proportion  to  the  amount  added. 

The  glands  of  internal  secretion  play  a  great  role  in  growth  as  well 
as  in  nutrition.  The  addition  of  thyroid  extract  to  the  food  of  the  cretin 
revolutionizes  not  only  his  metabolism  but  his  growth,  and  with  it  his 
appearance,  his  physical  and  mental  development.  According  to  Brails- 
ford  Robertson  C'),  tethelin,  a  substance  obtained  from  the  anterior  lobe 
of  the  pituitary,  plays  the  leading  part  in  the  control  of  growth.  The 
pituitary  came  under  suspicion  naturally  in  this  connection  owing  to  the 
intimate  association  of  gigantism,  infantilism,  acromegaly,  and  obesity 
to  tumors  of  the  hypophysis.  Other  glands  such  as  the  thymus  and  the 
gonads  unquestionably  are  concerned  also  to  some  extent. 

Energetics 

Energy  is  the  capacity  for  doing  work.  Energy  characterizes  life. 
The  ultimate  source  (jf  energy  is  the  sun ;  the  immediate  source  for  the 
living  body  is  its  nutriment.  Various  classes  of  food  have  different  food 
values,  but  equal  heat  values  do  not  of  necessity  have  equal  free  energy 
values,  for  energy  is  of  two  kinds,  bound  and  free,  only  the  latter  being 
available  for  actual  work.  The  total  energy  is  constant,  the  bound  tends 
to  a  maximum,  therefore  the  free  tends  to  diminish.  Some  foods  are 
more  easily  metabolized  than  others,  and  their  energy  is  quickly  avail- 
able.   Free  energy,  the  ability  to  do,  is  the  object  of  life. 

In  life,  physical  forces  are  controlled  largely  by  chemical  transforma- 
tions. Energy  results  from  chemical  exchange  and  is  comprised  of  two 
factors,  "  intensity  "  and  "  capacity  "  factors.  Chemical  energy  can  be 
converted  into  other  forms  without  passing  through  heat,  just  as  it 
does  in  a  battery.  Faraday  demonstrated  that  the  quantity  of  electricity 
obtained  from  a  Voltaic  cell  is  proportional  to  the  amount  of  chemical 


FACTORS  OF  PROGRESS  IN  THERAPY  889 

change.  Bayliss  (")  believes  that  chemical  energ-y  is  the  quantity  of  a 
substance  "  capacity  factor  "  multiplied  by  its  chemical  potential,  or 
"  affinity,"  and  that  the  capacity  factor  of  chemical  and  electrical  energy 
is  proportional,  and  further,  that  the  intensity  factors  are  also  pro- 
portional. In  other  words,  he  agrees  with  Faraday  in  regarding  elec- 
trical force  and  chemical  affinity  as  one  and  the  same  thing. 

The  transformation  from  chemical  to  dynamic  energy  appears  to  the 
writer  a  fruitful  field  for  investigation.  The  chemistry  of  nutrition  is 
relatively  well  understood,  but  the  conversion  of  chemical  forces  into 
energy  and  activities  so  vital  to  life  are  poorly  understood.  Heats  of 
combustion  do  not  entirely  suffice.  They  do  not  render  accurate  informa- 
tion as  to  the  energy  available  in  the  organism.  Bayliss  says,  for 
example,  that  it  is  necessary  to  know  if,  calorie  for  calorie,  carbo- 
hydrates have  a  greater  energetic  value  than  fats.  Such  information 
would  render  dietetics  of  infinitely  greater  value. 

The  problem  is  difficult,  but  fundamental.  One  great  difficulty  is 
the  number  of  factors  to  be  considered  and  the  consequent  complexity. 

The  amount  of  metabolism  controls  the  amount  of  oxygen  needed. 
The  amount  of  oxygen  needed  controls  the  work  of  the  lungs  and 
heart,  respiration  and  circulation.  Thus  the  fast  heart  of  exophthalmic 
goitre  and  of  fever  is  due  to  increased  rate  of  metabolism,  and  the  slow 
pulse  encountered  during  starvation  in  the  diabetic  is  probably  due  to  a 
decreased  rate  of  metabolism. 

Influence  of  the  Nervous  System 

In  early  embryonic  life,  nutrition  is  carried  on  without  the  existence 
of  a  demonstrable  nervous  system,  but  at  an  early  stage  of  development 
the  nervous  system  begins  to  exert  an  important  influence  on  the 
processes  of  growth  and  development.  This  is  most  strikingly  evidenced, 
perhaps,  in  the  function  of  growth  in  anterior  poliomyelitis.  The  mind 
naturally  turns  to  the  question  of  trophic  nerves.  Unquestionably, 
interference  with  the  nerve  supply  to  a  muscle  may  be  followed  by 
atrophy,  but  the  atrophy  is  not  of  necessity  due  to  the  nutritional  dis- 
turbance occasioned  directly  by  lack  of  proper  nerve  supply.  Herpes 
zoster  is  difficult  to  explain  otherwise  than  on  the  basis  of  direct  influence 
of  the  nervous  system  involving  metabolism  of  the  part  supplied.  The 
possibility  of  direct  nervous  control  of  metabolism  cannot  be  denied,  but 
on  the  other  hand,  proof  of  the  same  is  still  lacking.  The  growth  of 
tissue  in  Locke's  solution  outside  of  the  body  proves  the  possibility  of 
nutrition  and  growth  aside  from  nervous  influences. 

The  blood  supply  to  a  part  unquestionably  plays  a  determining  role 
in  its  metabolism,  and  thus  indirectly  at  least  the  nervous  system  is 


890     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

important.     It  is  possible  that  vasomotor  control  is  a  principal  factor 
through  regulation  of  blood  supply. 

The  question  of  the  role  of  the  nervous  system  is  deserving  of  the 
greatest  consideration.  The  intimacy  between  the  sympathetic  systems 
and  the  ductless  glands  suggests  related  functional  activity.  Before  the 
days  of  "  hormone  activity  "  attempts  were  made  to  correlate  the  activi- 
ties of  the  various  endocrine  glands  through  nervous  channels.  Diffi- 
culties encountered  in  establishing  such  relationships  made  it  necessary 
to  look  elsewhere,  with  the  result,  the  discovery  of  hormones. 

Emotions 

Similarly  emotions,  fright,  anger,  and  pain,  which  heretofore  have 
been  looked  upon  as  nervous  or  mental  attributes,  have  assumed  within 
later  years  a  much  broader  aspect.  One  hormone  at  least  is  of  great 
importance  in  this  connection.  Additional  information  concerning  the 
function  of  the  sympathetic  system  and  endocrine  glands  must  precede  a 
solution  of  many  questions  of  nutrition  and  metabolism. 

Since  the  nervous  system  is  one  of  the  controlling  factors  in  the 
function  of  the  endocrine  organs,  it  must  of  necessity  play  a  leading  role, 
at  least  indirectly.  In  the  absence  of  the  nervous  system,  normal  func- 
tion is  impossible. 

The  endocrine  glands  play  a  leading  role  in  the  control  of  metabolism, 
nutrition  and  growth,  and  bodily  dynamics.  The  most  important  are  the 
th}Toid,  suprarenal,  and  pituitary  glands.  The  influence  of  drugs  in 
this  connection,  though  marked,  has  never  been  satisfactorily  explained 
from  a  fundamental  point  of  view.  The  influence  of  adrenalin  and  to  a 
lesser  extent  of  strychnine  and  caffeine  in  removing  the  feeling  of  physi- 
cal exhaustion  as  the  result  of  prolonged  work  is  intimately  associated 
with  the  question  of  dynamics  and  energetics.  The  work  of  Cannon  (*®) 
and  Crile  (*^)  on  internal  secretions  and  emotions  brings  the  problem  into 
the  limelight  and  indicates  its  importance.  In  these  fields,  fundamental 
processes  are  being  revealed  and  the  foundation  of  science  being  laid  on 
which  will  be  built  the  medical  treatment  of  the  future. 

The  Relation  of  Thyroid  Function  to  Metabolism  and  Disease 

So  long  as  the  thyroid  is  normal  in  size  and  function,  it  is  of  no 
particular  interest  to  the  practicing  physician.  Meckel  in  1806  noted  that 
it  enlarged  during  menstruation  and  pregnancy,  which  suggested  a  close 
relationship  between  it  and  the  female  gonads.  The  first  important  con- 
tributions to  our  knowledge  of  the  thyroid  were  made  by  practicing 
physicians.  In  the  posthumous  writings  of  Parry  C^),  1825,  a  fashion- 
able physician  of  Bath,  is  a  description  of  eight  cases  of  "  Enlargement 


FACTORS  OF  PROGRESS  IN  THERAPY  891 

of  the  Thyroid  Gland,  in  connection  with  Enlargement  or  Palpitation  of 
the  Heart."  In  describing  the  first  cases,  1786,  he  writes,  "The  eyes 
were  protruded  from  the  sockets,  and  the  countenance  exhibited  an 
appearance  of  agitation  and  distress,  especially  on  any  muscular  move- 
ment." The  pulse  rate  was  150.  In  speaking  of  the  heart,  he  says,  "  It 
was  so  vehement  that  each  systole  of  the  heart  shook  the  whole  thorax." 
The  salient  features,  the  rapid,  overacting  heart,  the  exophthalmos,  the 
struma,  and  the  anxiety  are  all  clearly  depicted.  It  is  extremely  inter- 
esting to  note  that  the  dynamic  and  stress  features  are  portrayed  in  the 
original  description.  Graves  ("),  a  great  clinical  teacher,  and  Base- 
dow (^"),  a  general  practitioner,  also  described  the  same  disease  in  1835 
and  1840,  respectively;  Graves'  original  description  being,  "  A  lady,  aged 
21,  became  affected  with  some  symptoms  which  were  supposed  to  be 
hysterical.  ...  After  she  had  been  in  this  nervous  state  about  three 
months,  it  was  observed  that  her  pulse  had  become  singularly  rapid." 
Basedow  was  the  first  to  attempt  a  physiological  explanation  of  the 
manifestations  of  exophthalmic  goitre. 

Many  years  later,  in  1873,  Gull  (^^),  another  noted  English  physician, 
described  the  condition  known  as  myxedema,  and  in  1877,  Ord  C*) 
established  its  relationship  to  thyroid  activity.  Some  six  years  later, 
Kocher  (^^)  described  a  cachexia  strumapriva  occurring  in  thirty  per  cent, 
of  cases  after  the  removal  of  thyroid  in  goitre,  but  this  was  a  year  after 
the  Reverdins  had  described  the  same  condition  under  the  name,  "  myx- 
edema post  operatoire,"  Still  later,  von  Brunn  established  the  relation- 
ship of  cretinism  to  decreased  thyroid  activity.  The  early  experimental 
work  blocked,  rather  than  aided,  progress  until  the  functions  of  the  para- 
thyroid were  established  and  this  factor  covered  in  experimental  surgical 
procedures.*  Schiff  {^^)  and  Horsley  (")  both  demonstrated  that  trans- 
plantation of  the  thyroid  prevented  the  effects  of  removal.  Finally  came 
the  discovery  of  Murray  (^^)  and  of  Howitz  that  feeding  of  the  gland 
results  in  the  cure  of  myxedema. 

The  thyroid  is  an  extremely  vascular  ductless  gland,  a  single  organ 
composed  of  two  lateral,  frequently  unsymmetrical  masses  or  lobes  con- 
nected by  a  transverse  median  band  or  isthmus.  Its  nerves  are  probably 
all  derived  from  the  sympathetic  and  accompany  the  arteries  to  the  gland. 
The  true  thyroid  develops  as  an  unpaired  hollow  outgrowth  from  the 
foregut,  ventrally  to  the  branchial  arches  and  in  the  middle  line.  It  has 
its  origin  therefore  from  the  epithelium  of  the  buccal  cavity. 

Function  of  the  Thyroid. — It  exercises  an  important  control  over  the 
processes  of  nutrition  of  the  body,  and  especially  over  the  nervous  system. 

*  Schiff  described  the  results  of  complete  thyroidectomy  in  animals  in   1859. 


892      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

How  is  the  control  exerted?  Several  opinions  have  been  held:  (i)  The 
thyroid  elaborates  an  internal  secretion  characterized  by  a  large  iodine 
content  which  is  given  off  to  the  blood  and  lymph,  is  transported  to  the 
tissues,  and  there  exercises  a  regulating  function.  This  is  borne  out  by 
excision  of  the  organ,  and  by  pathological  processes  leading  to  its  destruc- 
tion as  evidenced  by  the  development  of  cretinism,  myxedema,  and 
thyreopriva,  and  by  the  close  parallelism  existing  between  hyperplasia  of 
the  thyroid  and  clinical  manifestations  of  toxicity,  (2)  The  thyroid 
secretion  neutralizes  or  destroys  toxic  substances  arising  in  metabolism 
in  the  same  manner  that  the  liver  overcomes  the  toxic  properties  of 
ammonia  through  converting  it  into  urea.  Following  removal  of  the 
thyroid,  toxic  substances  accumulate,  cause  toxic  manifestations  and 
result  in  death.  For  support  of  this  hypothesis,  proof  is  entirely  lacking. 
(3)  Still  another  view  was  put  forward  by  Cyon,  and  is  deserving  of 
some  consideration.  On  account  of  its  extreme  vascularity,  he  believes 
that  it  acts  as  "  a  vascular  shunt,  or  flood  gate  to  protect  mechanically 
the  circulation  in  the  brain."  This  is  reflexly  effected  through  the  hypo- 
physis cerebri,  and  the  vagi.  This  theory,  though  unacceptable  in  its 
entirety,  recognizes  the  relation  of  the  thyroid  and  its  internal  secretion 
to  distribution  and  the  total  blood  supply.  In  the  present  state  of  knowl- 
edge, it  is  probable  that  the  thyroid  does  control  blood  supply,  not 
directly,  but  secondarily  through  control  of  the  rate  of  metabolism.  It 
is  metabolism  which  controls  the  work  of  the  heart.  The  vascular  phe- 
nomena of  exophthalmic  goitre  may  be  looked  upon  as  resulting  from 
correlated  influences  on  the  vasomotor  mechanism.  The  heart  works  at 
its  maximum,  and  the  peripheral  circulation  is  thrown  wide  open  to  pro- 
vide a  maximum  blood  supply. 

The  point  of  contact  or  seat  of  action  of  the  internal  secretion  has 
not  yet  been  determined.  Whether  thyroxin  acts  directly  on  the  cells  of 
the  body,  or  through  their  nerve  supply  still  remains  to  be  settled. 

The  body  is  like  the  social  organism  at  large;  "no  man  liveth  unto 
himself  alone."  The  function  of  the  thyroid  is  internally  related  to  the 
function  of  the  body  as  a  whole.  Disturbance  of  its  function  disarranges 
function  as  a  whole.  Medicine  has  adopted  an  anatomical  viewpoint  in 
relation  to  disease.  But  for  a  true  grasp  of  disease  and  its  manifesta- 
tions, this  functional  conception  is  a  requisite. 

In  treatment  of  diseases  of  the  thyroid,  the  fundamental  question  is 
not  so  much  whether  it  is  an  adenoma,  colloid  goitre,  or  exophthalmic 
goitre,  but  whether  or  not  the  active  principle  of  the  thyroid  is  over- 
stimulating  or  failing  to  stimulate  metabolism;  in  other  words,  whether 
we  are  dealing  with  hypo-  or  hyper-activity  or  perversion  of  function. 

Obviously  it  is  desirable  to  know  the  nature  of  the  active  principle 


FACTORS  OF  PROGRESS  IN  THERAPY  893 

of  the  thyroid  and  the  mechanism  of  its  action.  Recent  work  has  shed 
much  hght  on  the  former  subject. 

Chemistry  of  the  Thyroid. — Kocher,  with  his  vast  cHnical  experience 
in  goitre,  surmised  that  the  thyroid  contained  an  iodine  combination 
because  of  the  clinical  effects  of  iodine  preparations  on  goitres.  In  1896, 
Baumann  (^")  isolated  a  colloid  substance  which  he  called  iodothyreo- 
globulin,  demonstrated  its  organic  character,  that  the  gland  contained 
several  milligrams  of  iodine,  and  further  that  the  thyroid  was  several 
times  richer  in  iodine  than  any  other  tissue  of  the  body.  Subsequently, 
through  the  work  of  Ostwald,  the  protein  nature  of  the  compound  was 
revealed.  The  desiccated  gland  was  found  to  be  largely  composed  of 
this  material,  and  its  activity  was  in  proportion  to  its  iodine  content. 

The  brilliant  work  of  Kendall  C")  has  resulted  in  the  isolation  of  the 
active  principle  of  the  thyroid  in  crystalline  form,  and  in  the  recognition 
of  its  chemical  nature.  In  describing  the  compound,  Kendall  says, 
"  Analysis  has  shown  that  it  contains  an  indol  group  with  the  iodine 
undoubtedly  attached  to  the  benzene  ring,"  and  "  that  on  the  carbon  atom 
adjacent  to  the  amino  group  of  the  indol  ring  there  is  an  oxygen  atom." 
He  ascribes  to  it  the  formula, 

H    ICH  H     H       ^^ 

7cy\c=c  -c— c— c 

^    ^  ^       ■        H     H      \ 


?cLU( 


TT     I       1       J  ^S 


\      o 
H 

He  lays  emphasis  on  the  oxyindol  nature  of  the  compound,  and  on 
the  CO  and  NH  radicles,  and  not  on  its  iodine  content.  The  substance 
was  named  thyroxyindol  or  thyroxin  for  short.  The  importance  of  the 
CO  and  NH  groups  is  revealed  by  the  disappearance  of  the  characteristic 
physiological  properties  on  substituting  an  acetyl  group  for  the  H  of  the 
amino  radicle.  "  Investigation  of  the  acetyl  derivative  showed  that  in 
alkaline  solutions  the  indol  form  of  the  compound  no  longer  exists,  but 
that  there  is  hydrolysis  of  the  CO  and  the  NH  groups,  resulting  in  the 
opening  of  the  ring  and  the  formation  of  COOH  and  NH2, 

H     H        ^O 
C==C  — C  — C  — C 

I       H     H        NqH 
C         C  =  0  "^ 

\        I 
N    OH 

H        H 


894      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

Further  investigation  showed  that  the  thyroxin  behaved  in  the  same 
way,  and  that  it  exists  within  the  body  not  in  the  closed  ring  form  such 
as  is  present  in  indol,  but  in  the  form  of  COOH  and  NH2." 

This  obviously  accounts  for  the  failure  of  physiological  activity  on 
substituting  an  acetyl  group  for  the  H  of  the  amino  radicle.  Kendall 
further  calls  attention  to  the  analogy  between  the  open  and  closed  forms 
of  thyroxin,  and  the  open  and  closed  forms  of  creatin  and  creatinin,  and 
states  that  the  same  relation  exists  between  amino-acids,  per  se,  and  the 
form  in  which  amino-acids  exist,  united  in  protein.  He  considers  the 
CONH  and  the  COONH2  nuclei  important  desiderata  in  the  production 
of  energy  in  protein  metabolism.  Synthesis  of  the  product  has  been  ac- 
complished, the  resulting  compound  exhibiting  all  the  chemical  and  physi- 
ological properties  of  the  substance  isolated  from  the  gland. 

The  question  naturally  arises,  does  the  thyroid  synthesize  thyroxin, 
or  does  it  serve  merely  as  a  storage  and  distributing  center  as  the  liver 
does,  for  instance,  in  relation  to  glycogen  and  dextrose  ?  The  available 
facts  are:  (i)  the  iodine  is  found  in  the  gland  in  large  quantities;  (2) 
that  the  quantity  is  variable,  even  in  health;  (3)  that  it  exists  in  colloidal 
state  as  a  protein  combination,  iodothyreoglobulin ;  (4)  that  this  latter  is 
not  a  chemical  entity;  (5)  that  the  desiccated  gland  varies  in  its  iodine 
content  and  its  activity  is  dependent  quantitatively  upon  its  iodine  con- 
tent; (6)  that  the  iodine  content  of  the  thyroid  varies  in  disease;  (7) 
that  a  definite  chemical  entity,  thyroxin,  has  been  isolated  from  the  gland 
in  crystalline  state;  (8)  that  thyroxin  counteracts  the  effects  of  thy- 
roidectomy in  animals,  and  in  extremely  small  quantities  causes  striking 
improvement  in  human  cases  of  myxedema  and  of  sporadic  cretinism; 
(9)  that  its  effect  in  raising  metabolism  is  quantitative  in  character, 
reaching  its  maximum  after  an  appropriate  dose,  only  after  some  days, 
and  persisting  for  some  weeks  after  a  single  injection;  (10)  that  its 
activity  is  not  dependent  entirely  on  its  iodine  content.  Whether  the 
hormone  of  the  thyroid  is  synthesized  or  merely  stored  in  the  gland  has 
not  yet  been  determined,  and  must  be  left  to  the  future  to  decide. 

Little  is  known  as  to  the  mechanism  of  action  of  the  thyroid.  The 
smallness  of  the  dose  of  thyroxin  and  its  marvelous  effect  in  accelerating 
metabolism  naturally  suggests  catalysis.  Catalytic  differs  from  enzymatic 
activity  in  that  the  latter  is  destroyed  at  relatively  low  temperature,  and 
is  as  a  rule  markedly  specific  in  character. 

The  characteristic  actions  of  a  catalyst  are:  (i)  that  it  accelerates 
chemical  action;  (2)  that  relatively  small  quantities  sufifice,  and  beyond 
certain  limits  further  increase  in  the  catalyst  does  not  further  accelerate 
the  action;  (3)  that  it  acts  only  by  its  presence,  and  it  does  not  itself 
participate  in  the  reaction  (with  certain  exceptions),  or  at  least  it  does  not 


FACTORS  OF  PROGRESS  IN  THERAPY  895 

form  part  of  the  resulting  system  in  the  final  equilibrium;  (4)  that  it 
acts  over  and  over  again,  and  that  as  a  rule  it  is  destroyed  or 
"  removed  from  the  sphere  of  action  in  the  form  of  constituents  of  some 
of  the  subsidiary  reactions";  (5)  and  that  when  the  system  is  one  that 
reaches  a  definite  equilibrium  under  the  conditions  of  the  experiment,  the 
position  of  this  equilibrium  is  unaffected  by  the  presence  or  the  amount 
of  the  catalyst,  which  merely  hastens  the  time  taken  by  the  process  and 
this  in  proportion  to  its  concentration  up  to  a  certain  point. 

Two  important  things  are  shown  by  these  facts;  namely,  that  the 
catalyst  does  not  supply  or  remove  energy  from  the  system,  and  that  it 
accelerates  both  the  hydrolytic  and  synthetic  components  of  a  reversible 
reaction.  Thyroxin  fulfills  most  of  these  requirements,  in  that  it  in- 
creases the  rate  of  metabolism,  acts  in  small  quantities,  increasingly 
more  with  somewhat  larger  quantities,  acts  over  a  period  of 
some  weeks  from  a  single  dose  so  that  in  all  probability  it  acts 
repeatedly,  and  finally,  in  that  it  does  not  modify  the  type  but  only  the 
rate  of  metabolism  so  far  as  can  be  ascertained.  Against  its  catalytic 
activity  can  be  argued  the  slowness  with  which  its  effect  is  exerted,  the 
maximum  not  being  reached  for  several  days,  and  the  evident  dynamic 
effect  in  increasing  the  energy  of  the  individual.  The  latter,  however, 
is  secondary;  not  the  result  of  the  increase  of  the  chemical  reaction, 
per  se,  but  of  the  restoration  of  normal  function  as  the  result  of  normal 
metabolism. 

The  seat  of  action  of  the  active  principle  of  the  thyroid  is  still  a 
matter  of  discussion.  Is  its  function  carried  on  in  the  gland  through 
the  nervous  system,  or  in  the  cells  of  the  body  generally?  It  seems 
probable  that  the  gland  acts  as  a  storehouse,  and  gives  off  the  active 
principle  which  acts,  as  Plummer  believes,  on  the  cells  of  the  body 
generally,  both  directly  and  indirectly. 

The  gland  itself  is  subject  to  control.  It  is  influenced  by  other  glands 
of  internal  secretion,  and  also  by  the  sympathetic  nervous  system.  The 
work  of  Cannon,  in  which  overactivity  of  the  thyroid  was  obtained 
through  continuous  stimulation  of  the  sympathetic,  through  transplanta- 
tion of  the  phrenic  into  the  cervical  sympathetic,  established  the  impor- 
tance of  the  sympathetic  system  in  relation  to  the  function  of  the  thyroid. 

Clinically,  the  anamnesis  of  exophthalmic  goitre  is  usually  a  history 
of  prolonged  nervousness.  Its  clinical  manifestations  include  many  and 
marked  evidences  of  the  involvement  of  the  sympathetic.  Barker  says, 
"  Among  the  symptoms  largely  referable  to  the  autonomic  nervous 
system  are  included:  (a)  the  eye  signs;  (b)  the  cardiovascular  phe- 
nomena; (c)  the  cutaneous  phenomena;  (d)  the  digestive  disturbances; 
(e)  the  respiratory  disturbances;  and  (f)  the  urogenital  symptoms." 


896     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

Similarly,  infection,  local  or  general,  exercises  a  marked  influence  on 
the  thyroid,  and  upon  metabolism.  This  knowledge  is  born  of  clinical 
experience  which  reveals  the  closest  connection  between  acute  or  chronic 
infections  and  manifestations  of  Graves'  disease. 

Before  discussing  the  diseases  of  the  thyroid,  a  survey  of  the  clinical 
manifestations  following  the  removal  of  the  thyroid  and  those  of  Graves' 
disease  cannot  fail  to  impress  one  with  the  significance  of  the  role  of 
the  thyroid.  In  fact,  the  contrast  was  in  large  part  responsible  for  the 
present-day  view,  that  the  thyroid  itself,  through  overactivity,  is  a 
primary  factor  in  Graves'  disease.  Kocher  has  tabulated  the  following 
facts : 


Cachexia  Thyreopriva 
Absence  of  atrophy  of  the  thyroid  gland. 

Slow,  small,  regular  pulse. 

Cold  skin   without  flushings. 

An  uninterested,  quiet  stare  without  ex- 
pression of  life. 

Narrow  palpebral  aperture. 

Slow  digestion  and  excretion,  poor  ap- 
petite,   requiring   little    food. 

Retarded  metabolism. 

Skin  is  thick,  opaque,  folded,  dry,  and 
scaling. 

Short,  thick  fingers  with  broad  ends. 

Sleepy. 

Dulled  sensation,  apperception,  and  action. 

Lack  of  thoughts,  interest,  and  emotion. 

Slow,  awkward  muscular  movements. 

Stiffness  of  the  extremities. 

Delay    in    growth    of    bones,    often    with 

deformities.     Bones  thick  and  soft. 
Constant  chilliness. 
Slow,  deep  breathing. 

Increase  in  weight. 

Aged  appearance,  even  of  young  people. 


Graves'  Disease 

Swelling  of  the  thyroid  gland,  usually  of 
a  diffuse  nature.     Hypervascularization. 
Rapid,  full,  and  at  times  irregular  pulse. 
Irritable  vasomotor  system. 
Anxious  appearance,  angry  expression. 

Wide  palpebral  aperture,  exophthalmos. 

Abundant  excretions,  an  excessive  appe- 
tite, with  increased  needs  of  food. 

Increased  metabolism. 

Skin  is  thin,  transparent,  finely  mjected, 
and  moist. 

Long  slender  fingers  with  pointed  ends. 

Wakeful  and  disturbed  sleep. 

Increased  sensation,  apperception,  and  ac- 
tion. 

Flight  of  ideas,  psychic  excitation  even  to 
hallucination,  mania,  and  melancholia. 

Constant  activity  and  haste. 

Tremor,  and  increased  mobility  of  joints. 

Slender  skeleton  with  here  and  there  soft 
bones. 

Unbearable  feeling  of  heat. 

Superficial  breathing  with  imperfect  in- 
spiratory expansion. 

Loss  of  weight. 

Youthful  appearance,  especially  at  the 
onset. 


Hypothyroidism. — There  are  three  types  of  hypothyroidism.  The 
first  described  was  spontaneous  myxedema.  As  already  indicated,  sur- 
gical removal  of  the  thyroid  in  goitre  led  to  the  recognition  of  myx- 
edema "  post  operatoire  "  while  later,  cretinism  was  recognized  and  also 
its  relationship  to  the  thyroid.  According  to  Osier,  credit  is  due  to  Felix 
Simon  for  recognizing  that  these  were  all  one  and  the  same  disease,  and 
all  due  to  loss  of  function  of  the  thyroid  gland.  They  have  in  common 
nutritional  disturbance,  mental  retardation,  changes  in  tegumental  struc- 
tures, and  edematous  or  mucous  deposits. 


FACTORS  OF  PROGRESS  IN  THERAPY  897 

Myxedema  may  occur  spontaneously  or  subsequent  to  operative 
removal  of  the  thyroid.  The  name  myxedema  was  employed  because  of 
the  peculiar  edematous-like  swellings  observed  in  the  cutaneous  and  sub- 
cutaneous and  other  tissues.  These  swellings  differ  from  ordinary  edema 
in  that  they  are  firmer,  and  do  not  pit  on  pressure,  and  in  that  histologi- 
cally they  show  a  mucin-like  material. 

The  disease  is  characterized,  according  to  Ord,  who  established  its 
etiology,  by  marked  increase  in  the  general  bulk  of  the  body,  a  peculiar 
firm  swelling  or  edema  of  the  skin,  which  does  not  pit  on  pressure,  dry- 
ness and  roughness  of  the  skin  (which,  together  with  the  swelling,  tends 
to  obliterate  the  normal  hues  of  the  face,  thus  resulting  in  a  peculiar 
physiognomy  which  is  often  pathognomonic),  and  finally,  imperfect  nu- 
trition of  hair  and  nails.  The  features  become  coarse  and  expressionless, 
and  the  skin  takes  on  a  pallid,  waxy  appearance.  In  addition  to  physical 
changes,  there  is  generally  marked  mental  retardation,  suggesting  stupid- 
ity, at  times  lethargy  and  somnolence.  Slowness  in  movement  is  also 
striking.  Patients  complain  bitterly  of  being  cold.  This  is  worse  in  cold 
and  less  troublesome  in  warm  weather. 

The  onset  is  insidious,  slowly  progressive,  resulting  eventually  in  most 
instances  in  the  bodily  changes  already  described  and  in  asthenia,  loss  of 
capacity  for  work,  and  a  susceptibility  to  marked  mental  changes,  involv- 
ing suspicions,  delusions,  hallucinations,  and  occasionally  dementia. 
Instances  of  both  hyper-  and  hypo-activity  of  the  thyroid  have  been  noted 
from  time  to  time.  Myxedema  has  also  been  encountered  subsequent  to 
exophthalmic  goitre,  and  in  the  later  stages  of  adenoma  of  the  thyroid. 

The  postoperative  condition  is  infrequent  in  this  country.  After  com- 
plete thyroidectomy  it  occurs  in  seventy-five  per  cent,  of  cases  according 
to  Kocher,  who  advises  that  at  least  one-quarter  of  the  gland  be  left  if 
possible.  Its  features  are  identical  with  those  of  myxedema  proper.  It 
follows  operations  in  which  a  large  proportion  of  the  gland  is  removed, 
and  occasionally  in  less  marked  resections  in  patients  who  have  exhibited 
dysthyroidism. 

Skeletal  changes  such  as  are  seen  in  cretinism  are  rare  except  in  cases 
developing  in  youth  subsequent  to  one  of  the  febrile  diseases.  Through 
studies  of  the  rate  of  basal  metabolism,  decreases  of  from  ten  to  thirty  per 
cent,  are  revealed.  Formerly  such  studies  were  possible  only  in  special 
institutions,  but  now  that  indirect  calorimetry  has  been  made  simple  and 
reliable,  studies  of  metabolic  rate  are  being  made  in  many  clinics  through- 
out the  country. 

Cretinism. — Of  this  there  are  two  forms,  the  sporadic  and  the 
endemic,  only  the  former  occurring  in  America.  The  condition  may  be 
congenital,  due  to  absence  of  the  gland,  or  acquired,  due  to  atrophy, 


898      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

resulting  from  one  of  the  febrile  affections.  It  is  encountered  not  infre- 
quently. It  is  characterized  by  bodily  and  mental  retardation  and  by 
certain  skeletal  deviations  which  are  more  or  less  characteristic,  and 
which  indicate  that  the  thyroid  secretion  plays  a  role  in  relation  to  growth 
and  mental  development. 

Recognition  of  the  condition  is  usually  not  made  before  six  months 
of  age,  while  the  disease  is  well  marked  at  the  end  of  the  first  or  in  the 
second  years.  The  head  is  deformed  in  sporadic  cases,  long  in  the 
antero-posterior  diameter  (dolichocephalic).  The  body  is  undersized, 
dwarfed,  pudgy,  and  the  abdomen  protuberant.  The  face  is  that  of  an 
imbecile,  the  mouth  open,  the  tongue  large  and  protruding,  and  the  bridge 
of  the  nose  sunken.  The  fontanelles  close  late,  and  the  epiphyses  unite 
with  the  long  bones  late  or  not  at  all.  The  hands  and  feet  are  thick 
and  stubby.  Dentition  is  delayed.  Marked  weakness  exists,  so  that  the 
child  cannot  support  itself.  The  skin  is  thick,  pallid,  and  waxy,  the  hair 
thin,  and  subcutaneous  pads  such  as  are  seen  in  myxedema  occur  at 
times,  especially  about  the  cheeks.  Mentality  is  markedly  retarded,  and 
in  some  instances  imbecility  develops. 

Once  the  condition  has  been  seen  it  is  readily  diagnosed  as  a  rule. 
The  facial  expression,  the  skin  changes,  the  protruding  abdomen,  and  the 
physical  and  mental  retardation  at  once  suggest  cretinism.  Metabolic 
studies  reveal  a  lowered  metabolic  rate,  decrease  of  ten  to  forty  per  cent, 
below  normal. 

Treatment  of  Myxedema  and  Cretinism. — The  progress  in  the  treat- 
ment of  myxedema  exemplifies  the  rapidity  of  the  development  of  the 
science  of  therapeutics.  Results  regarded  as  impossible  a  century  ago, 
as  marvelous  two  decades  ago,  are  accepted  as  a  matter  of  course  today. 
Just  as  salvarsan  overshadows  the  mercury  treatment  of  syphilis,  so  thy- 
roxin supplants  older  methods,  owing  to  its  efficacy,  its  rapidity,  and  the 
manner  in  which  it  lends  itself  to  quantitative  study  and  control.  To 
revert  to  the  terminology  of  proprietary  medicine,  "  the  results  are 
startling."  In  some  instances  individuals  are  made  over  overnight.  No 
more  brilliant  therapy  exists  in  the  healing  art  today  than  in  deficiency  of 
the  thyroid  gland. 

The  fresh  gland,  desiccated  powder,  aqueous  and  glycerine  extracts 
are  all  efficacious  in  the  majority  of  cases  of  myxedema.  Numerous 
preparations  of  gland  are  marketed,  but  the  most  convenient  are  the  desic- 
cated gland  and  the  glycerine  extract.  The  powdered  gland  is  given  in 
0.065  S^-y  or  o"^  grain,  doses  three  times  a  day  in  the  beginning  and  in- 
creased to  0.651-  gm.,  or  10  to  15  grains  per  day.  Unpleasant  symptoms, 
irritation  of  the  skin,  restlessness,  tachycardia  and  delirium,  and  in  some 
instances  tonic  spasms  sometimes  accompany  its  use.    In  the  majority  of 


FACTORS  OF  PROGRESS  IN  THERAPY  899 

instances  no  untoward  effects  are  encountered.  Within  a  few  weeks  the 
marvelous  changes  referred  to  above  appear.  The  skin  becomes  soft, 
warm,  and  natural,  the  edema  disappears,  and  the  face  is  that  of  another 
individual.  No  less  striking  is  the  change  in  character  and  deport- 
ment; from  the  slow,  cumbersome,  sluggish  victim  of  myxedema,  there 
emerges  a  normal,  wide-awake  individual. 

Following  the  initial  intensive  treatment,  subsequent  intermittent  treat- 
ment with  small  doses  is  necessary  in  most  cases  of  myxedema,  and  in 
all  cases  of  cretinism.  Relapse  usually  follows  prolonged  absence  of  the 
drug. 

Treatment  with  thyroxin  is  a  matter  of  science.  It  deals  with 
accurate  measurement  of  the  drug,  of  the  rate  of  metabolism,  of  the  time 
element,  and  with  the  control  of  effects.  After  determining  the 
metabolic  rate,  the  dose  is  calculated  according  to  the  percentage  decrease 
of  metabolic  rate.  The  number  of  milligrams  of  thyroxin  required  is 
treated  with  10  per  cent.  NaOH,  diluted  with  distilled  water  and  adminis- 
tered intravenously.  With  marked  lowering  of  metabolism  (25-30%), 
10  to  15  milligrams  are  used,  while  with  a  sHght  decrease  (10-20%)  5 
or  sometimes  10  milligrams  are  used.  Each  milligram,  according  to 
Plummer,  raises  metabolic  rate  two  per  cent.  Metabolism  usually  reaches 
its  maximum  on  the  8th  or  12th  day,  maintains  a  plateau,  and  then 
gradually  decreases.  However,  the  writer  has  observed  a  rise  from 
below  twenty-seven  per  cent,  to  normal  metabolism  in  five  days  on  ad- 
ministering five  milligrams  in  a  single  dose  intravenously. 

Although  the  maximum  effect  on  metabolism  is  not  immediate,  that 
on  the  patient  may  be.  Cases,  typical  in  every  respect,  may  be  absolutely 
revolutionized  within  twenty-four  hours.  Plummer,  who  was  the  first  to 
use  thyroxin,  relates  his  great  surprise  on  his  first  visit,  subsequent  to 
treatment.  He  doubted  his  own  eyes.  On  the  other  hand,  metabolic  rate 
may  be  brought  to  normal  without  striking  concomitant  clinical  results, 
as  in  one  of  our  own  cases. 

Large  quantities  of  urine,  sometimes  amounting  to  several  liters,  are 
not  infrequently  passed  during  the  first  twenty-four  hours,  and  with  the 
polyuria,  the  edema  or  myxedema  of  the  skin  and  subcutaneous  tissues 
disappears.  Palpitation  is  apt  to  be  a  striking  phenomenon.  Headache 
is  frequently  a  marked  symptom,  and  occasionally  vomiting.  In  the  ma- 
jority of  cases  the  patient  appears  to  be,  feels,  acts,  and  is  a 
different  individual.  The  skin  resumes  its  softness,  perspiration  is 
reestablished,  and  the  patient  feels  warm  again,  sometimes  after  being 
cold  for  years. 

The  time  relationship  between  this  recovery  of  the  patient  and  the 
return  of  metabolism  to  normal  is  a  matter  of  great  interest,  but  no 


900     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

explanation  is  yet  apparent.     Subjective  and  objective  improvement  may 
precede  the  maximum  metabolic  rate  by  at  least  a  week. 

The  treatment  in  cretinism  is  identical  in  every  respect,  except  that 
smaller  doses  are  employed.  A  cretin  treated  with  thyroxin  by  us  was 
converted  within  a  short  period  from  a  slow  stupid  imbecile  to  the 
liveliest  and  most  interesting  youngster  in  the  ward,  the  result  of  two 
injections  of  2  mgms.  each. 

Hyperthyroidism. — Before  considering  hyperthyroidism  clinically, 
it  is  well  to  obtain  a  view  of  its  experimental  aspects.  Two  general 
methods  have  been  employed  in  its  production : 

(i)  The  administration  of  thyroid.  In  sufficient  doses,  toxicity 
appears  in  all  animals,  but  is  most  readily  produced  as  a  rule  in  the 
human.  Carnivorous  animals  are  least  affected.  In  man,  loss  of  weight 
is  one  of  the  most  constant  manifestations,  the  result  apparently 
of  increase  in  metabolism.  Skin  changes  are  common,  especially 
sweating,  which  is  accompanied  by  a  general  feeling  of  warmth. 
Tachycardia  is  of  common  occurrence  as  are  also  restlessness,  irrita- 
bility, excitability,  and  insomnia.  Trembling  is  frequent,  and  gas- 
trointestinal disturbances  common.  These  symptoms  are  observed  not 
infrequently  in  the  clinical  use  of  the  desiccated  gland,  and  lead  to 
its  discontinuation.  Motthafft's  patient,  mentioned  by  Hewlett,  a  fat 
man  of  43  years  who  took  about  1,000  tablets  in  the  course  of  five 
weeks,  developed  rapid  respiration,  slight  fever,  glycosuria,  and  bilateral 
exophthalmus,  in  addition  to  the  usual  manifestations  listed  above.  This 
is  perhaps  the  nearest  approach  on  record  to  the  experimental  pro- 
duction of  exophthalmic  goitre.  Exophthalmus  is  also  reported  by 
Beclere. 

In  animals,  emaciation,  increased  appetite,  thirst,  digestive  disturb- 
ances, and  exophthalmus  have  been  produced.  Glycosuria  has  resulted  in 
some  instances.  Increased  metabolism  is  a  constant  feature.  Similar 
effects  have  followed  the  administration  of  iodine  to  patients  suffering 
from  disease  of  the  thyroid;  loss  of  weight,  nervousness,  tachycardia,  and 
tremor  being  the  most  common  manifestations.  These  are  not  ordinary 
evidences  of  iodism  such  as  are  seen  in  normal  individuals,  and  they 
probably  result  from  the  effect  of  iodine  on  the  diseased  thyroid. 

(2)  Thyroid  stimulation  through  the  sympathetic  nervous  system. 
Cannon  and  his  associates  have  produced  hyperthyroidism  in  a  manner 
which  sheds  considerable  light  on  the  mechanism  involved.  The  phrenic 
was  cut  in  the  neck  in  cats  and  its  peripheral  end  was  anastomosed  into 
the  central  end  of  the  cut  cervical  sympathetic.  Subsequent  to  union, 
stimuli  from  the  constantly  active  diaphragm  supplied  the  sympathetic 
with  constant  stimulation.     Increased  excitability,  tachycardia,  diarrhea, 


FACTORS  OF  PROGRESS  IN  THERAPY  901 

exophthalmus,  and  high  rate  of  metabolism  were  induced.     The  symp- 
toms bore  a  striking  relationship  to  those  of  hyperthyroidism. 

Before  leaving  the  subject  of  the  effects  of  the  thyroid  on  metabolism 
and  growth,  the  brilliant  studies  of  Gudernatsch  should  be  mentioned. 
This  investigator  fed  thyroid  to  tadpoles,  and  showed  that  this  resulted 
in  stunting  of  the  growth  of  the  animal,  but  in  early  metamorphosis. 
The  limbs  appeared  early,  and  the  tail  disappeared  earlier  than  normal, 
long  before  the  tadpole  had  attained  the  size  at  which  this  usually  occurs. 
These  results  are  in  keeping  with  our  general  ideas  concerning  the  direct 
relation  of  the  thyroid  to  growth  of  the  soma  and  gonads. 

Exophthalmic  Goitre. — Hyperthyroidism  is  most  frequently  asso- 
ciated with  exophthalmic  goitre  or  toxic  adenomata.  The  former  is  a 
disease  characterized  by  goitre,  exophthalmus,  tachycardia,  tremor,  nerv- 
ousness, and  increased  metabolic  rate,  associated  with  a  perverted  or 
hyperactive  state  of  the  thyroid  gland. 

The  condition  has  been  looked  upon  by  many  as  a  pure  neurosis, 
because  of  the  prominence  of  nervous  manifestations  in  the  anamnesis, 
and  in  the  disease  itself,  and  because  of  its  development  in  many  instances 
after  nervous  and  emotional  strains.  At  present  it  is  usually  accepted 
as  a  disease  of  the  thyroid,  the  result  of  hyperactivity.  The  gland 
in  exophthalmic  goitre  suggests  great  activity,  extreme  vascularity,  with 
increased  proliferation  and  with  the  production  of  newly  formed  spaces 
and  absorption  of  the  colloid  material,  which  is  replaced  by  a  more 
mucinous  fluid.  The  importance  of  the  thyroid  itself  is  borne  out  by 
partial  thyroidectomy,  which  yields  much  better  results  than  any  other 
treatment  as  yet  suggested.  With  the  removal  of  thyroid  substance  the 
metabolism  returns  rapidly  to  normal,  and  the  symptoms  disappear.  U 
too  much  thyroid  tissue  is  removed  evidences  of  myxedema  develop, 
which  in  turn  can  be  removed  by  administration  of  the  desiccated  gland 
or  thyroxin.  On  the  other  hand,  the  disease  can  be  produced  experi^ 
mentally  through  nervous  influences  as  demonstrated  by  the  work  of 
Cannon.  It  must  be  admitted  that  at  the  present  time  the  seat  of  the 
primary  change  has  not  been  determined. 

The  disease  is  one  of  adult  life,  rarely  appears  before  puberty,  and 
affects  females  more  than  males.  Its  course  may  be  acute,  but  is  usually 
chronic.  The  main  clinical  manfestations  will  be  considered  in  some 
detail,  especially  their  pathogenesis,  in  order  to  learn  something  of  thc^ 
mechanism  involved  in  the  disease. 

Barker  classifies  the  symptoms  of  Graves'  disease  as  follows:  (i) 
the  goitre  or  struma;  (2)  symptoms  referable  to  the  autonomic  nervous 
system,  including  (a)  eye  signs,  (b)  the  cardiovascular  phenomena,  (c) 
the   cutaneous   phenomena,    (d)    the    digestive    disturbances,    (e)    the 


902     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

respiration  disturbances,  (f)  and  the  uro-genital  symptoms;  (3)  meta- 
bolic disturbances;  (4)  symptoms  referable  to  other  endocrine  glands; 
(5)  cerebral  s}Tnptoms;  and  (6)  blood  changes. 

The  gland  is  usually  enlarged  symmetrically,  but  not  necessarily  so. 
It  is  extremely  vascular,  as  evidenced  by  thrills  and  bruits.  Its  low  iodine 
content  is  difficult  to  explain  except  on  the  basis  that  the  gland  ordinarily 
stores  iodine,  which  function  is  lost  in  hyper-activity. 

In  typical  cases  metabolism  is  greatly  increased,  in  some  cases 
fifty  to  eighty  per  cent,  above  normal.  This  increase  is  exaggerated  by 
extreme  nei"vousness,  by  bodily  and  mental  overactivity.  These  are  prob- 
ably but  factors  in  a  vicious  circle.  The  skin  is  usually  warm  and  moist, 
and  fever  is  not  at  all  uncommon.  In  addition  to  total  metabolism, 
change  occurs  in  relation  to  carbohydrates  and  proteins. 

Tissue  catabolism  is  marked,  resulting  in  increased  nitrogen  excretion 
and  in  loss  of  weight.  Nitrogen  equilibrium  is  difficult  to  maintain. 
Alimentary  glycosuria  is  common.  The  explanation  for  this  is  not  clear, 
but  the  work  of  Cramer  and  Kraus  suggests  the  possibility  of  it  being  a 
deficiency  in  the  glycogenic  function  of  the  liver. 

The  possibility  of  the  tachycardia  being  due  to  stimulation  of  the 
accelerator  nerves  of  the  heart  is  not  at  present  entertained.  In  all 
probability  it  is  but  a  part  of  the  cycle  involved  in  increase  in  metabolism. 
The  heart  is  overactive  in  order  to  supply  sufficient  blood  to  the  over- 
metabolizing  tissues  generally.  The  rapid  circulation,  the  overacting 
heart,  the  high  systolic  and  low  diastolic  pressure,  the  high  pulse  pressure, 
capillary  pulsation,  and  vascular  erythema  are  all  incidental  features 
involved  in  the  effort  to  supply  sufficient  blood.  The  development  later 
of  myocardial  insufficiency,  of  dilation  and  arrythmias  are  but  natural 
sequences  of  overuse.  If  the  cardiac  control  is  of  nervous  origin  this  is 
probably  secondary  to  metabolic  states. 

The  exophthalmus  is  probably  due  to  relaxation  of  the  extra  ocular 
muscles  or  to  spasm  of  the  smooth  muscle  fibers  described  by  Miiller. 
Their  function  in  contraction  is  to  protrude  the  eyeball  and  pull  back  the 
lids,  and  it  is  carried  out  through  fibers  from  the  cervical  sympathetic. 
The  possibility  of  localized  edema  of  the  orbit  seems  unlikely  to  the 
writer,  though  the  presence  of  fat  as  the  explanation  of  the  failure  of 
disappearance  of  exophthalmus  after  cure  in  long-standing  cases  appears 
quite  reasonable. 

The  tremors  are  unexplained,  unless  they  are  accepted  as  evidence  of 
the  tense  overwrought  nervous  system  or  secondary  to  concomitant 
involvement  of  the  parathyroids.  The  nervous  manifestations  indicate 
that  the  nervous  system  is  involved  in  the  process  primarily  or  second- 
arily.    They  appear  early,  as  a  rule,  and  occasion  great  discomfort  to 


FACTORS  OF  PROGRESS  IN  THERAPY  903 

the  patient.  As  already  indicated,  they  trequentl\-  result  from  the 
administration  of  thyroid.  Increased  metabolic  rates,  such  as  are  encoun- 
tered in  febrile  conditions,  are  not  infrequently  also  accompanied  by 
similar  nervous  symptoms  (Barker). 

The  disease  is  one  of  several  years'  duration.  After  persisting  several 
months,  symptoms  may  disappear  to  reappear  again  at  a  later  date. 
Clinically,  the  effect  of  infections  is  most  striking.  Thus  a  mild  attack 
of  tonsillitis  may  occasion  an  acute  marked  exacerbation  of  the  Graves' 
disease  which  in  some  instances  disappears  as  the  local  condition  clears 
up,  or  more  frequently  subsides  slowly  in  the  course  of  a  few  weeks  or 
months.  Similarly,  emotions  and  nervous  strains  are  prolific  sources  of 
acute  exacerbation. 

Plausible  explanations  can  be  found  for  the  clinical  manifestation  in 
typical  cases.  But  atypical  cases  abound.  In  the  early  stages  of  the 
disease,  the  diagnosis  is  most  difficult  at  times.  In  the  same  indi- 
vidual,'striking  evidences  for  over-  and  under-function  of  the  thyroid 
are  not  at  all  infrequent.  One  or  another  feature  may  be  strikingly  exag- 
gerated or  entirely  wanting.  It  is  the  inability  to  explain  the  bizarre 
combinations  of  clinical  findings  in  the  individual  case  that  makes  the 
clinician  skeptical  of  theories  and  chary  of  accepting  one  chemical  entity 
as  the  active  principle  of  the  thyroid.  Correlations  of  laboratory  investi- 
gations with  clinical  studies  serve  to  increase  this  skepticism  at  times. 
Normal,  or  even  decreased  metabolic  rates  are  encountered  at  times  with 
clinical  pictures  very  suggestive  of  Graves'  disease  or  of  thyrotoxicosis. 

There  is  a  feature  of  Graves'  disease  that  baffles  expression.  It  is 
revealed  in  the  facial  expression,  in  the  incessant  restlessness,  the  over- 
whelming nervous  strain,  and  in  the  pent-up  feeling.  It  is  kinetic, 
dynamic,  a  hidden  fire.  I  am  always  reminded  by  a  case  of  this  kind  of 
a  motor  car,  gear  in  neutral,  brakes  set,  but  with  the  engine  still  running. 
Even  at  rest,  the  throb  of  life  is  evident,  combustion  is  going  on,  energy 
is  being  dissipated  or  is  felt,  but  it  is  not  being  utilized  ;  and  back  of  it  all 
one  recognizes  that  fuel  is  being  consumed,  that  energy  is  wasted,  and 
that  the  engine  is  being  subjected  to  useless  wear  and  tear.  Such  factors 
must  be  approached  through  studies  in  energetics,  dynamics,  and  kinetics, 
living  forces  as  yet  but  little  understood. 

Treatment  of  Hyperthyroidism 

(a)  If  we  accept  the  theory  of  overactivity  of  the  thyroid  as  the 
cause  of  exophthalmic  goitre  logically,  in  the  absence  of  effective  methods 
of  control  of  its  action,  we  are  forced  to  turn  to  partial  removal  of 
the  gland.  Practically  this  procedure  yields  the  best  results.  But  since 
operations  cannot  be  lightly  undertaken,  every  effort  must  be  made  to 


904      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

obtain  results  in  other  ways  until  such  time  at  least  as  the  operation 
appears  imperative. 

The  important  features  are  absolute  rest  in  bed,  and  freedom  from 
visitors.  An  ice  bag  is  placed  locally  over  the  thyroid,  and  another  over 
the  heart  if  it  is  tumultuous.  Digitalis,  or  strophanthus  are  indicated  for 
myocardial  insufficiency.  Many  drugs  have  been  advocated,  but  few  give 
outspoken  results.  Cacodylate  of  sodium  is  used  hypodermically  for  the 
lowering  of  metabolism,  although  proof  of  such  an  effect  is  lacking.  We 
have  observed  marked  decrease  in  metabolic  rate  coincident  with  its 
employment  but  whether  it  is  the  general  treatment  (rest,  diet,  etc.)  that 
played  the  greater  role  has  not  yet  been  determined. 

(b)  Milk  of  dethyroidized  goats  has  been  tried  as  has  also  serum 
of  animals  into  which  human  thyroid  extract  has  been  injected.  Some 
good  results  have  been  reported  from  both  these  methods,  but  they  have 
not  sufficient  effect  to  bring  them  into  general  use. 

(c)  Dietary  measures;  a  low  caloric  diet  with  a  more  than  propor- 
tionate decrease  in  proteins,  is  desirable  for  a  short  period  at  least. 

(d)  Local  injections  of  urea  solution  into  the  thyroid  gland  is  fol- 
lowed by  improvement  in  some  cases. 

(e)  Removal  of  foci  of  infection  exercises  a  beneficial  effect  at 
times. 

Ligation  of  vessels  suffices  in  many  cases,  but  in  the  majority  of 
instances  the  results  are  purely  temporary.  Partial  excision,  as  prac- 
ticed by  many  surgeons,  gives  much  the  best  results.  Recovery  is  rapid, 
and  complete  in  many  cases.  Excision  of  the  superior  cervical  sympa- 
thetic ganglia  has  also  been  practiced;  the  slight  ptosis  resulting,  serving 
to  alleviate  the  staring  expression  associated  with  the  exophthalmus. 

Two  procedures  practiced  by  surgeons  in  relation  to  thyroid 
operations  are  worthy  of  mention:  (i)  the  practice  in  certain  clinics 
of  observing  the  effect  of  the  visit  to  the  operating  room,  and  the  post- 
ponement of  the  operation  in  the  event  of  undue  excitement,  with  marked 
exacerbation  of  symptoms;  and  (2)  anoci  association,  which  was  intro- 
duced by  Crile  in  an  effort  to  protect  the  nervous  system  generally  from 
the  shock  of  the  operation.  These  indicate  the.  importance  which  the 
nervous  system  plays  in  the  experience  of  the  surgeon. 

The  thymus,  which  is  enlarged  in  a  considerable  percentage  of  thyroid 
cases,  has  been  subjected  to  systematic  X-ray  treatment.  The  results  as 
a  whole  have  been  disappointing.  Systematic  and  prolonged  treatment 
of  both  thymus  and  thyroid  has  yielded  some  brilliant  results. 

Here  again  in  the  treatment  of  thyroid  disease  the  basis  for  future 
drug  therapy  is  being  laid.  With  increasing  knowledge  of  metabolism 
chemical  control  of  these  processes  will  be  sought.    Means  of  chemically 


FACTORS  OF  PROGRESS  IN  THERAPY  905 

increasing  the  rate  of  metabolism  have  ah-eady  been  attained.  The  prob- 
lem of  finding  chemicals  capable  of  slowing  the  rate  of  metabolism  now 
confronts  us. 


(7)     Treatment  Based  on  a  Functional  Conception 

OF  Disease 

A  functional  conception  of  disease  as  a  basis  of  treatment  is  rapidly 
attaining  a  foothold  in  medicine.  From  the  vast  field  presented,  only 
one  example  will  be  considered.  This,  however,  will  be  discussed  in 
considerable  detail,  since  through  such  a  procedure  the  various  principles 
underlying  this  "form  of  treatment  can  be  presented. 

Myocardial  InsufUciency 

The  function  of  the  heart  is  to  keep  the  blood  circulating,  sending  it: 
(i)  to  the  lungs  where  it  rids  itself  of  its  CO2,  and  takes  up  oxygen; 
(2)  to  the  tissues  where  it  supplies  oxygen  and  nutriment,  and  takes  up 
waste  material;  (3)  to  the  gastrointestinal  tract  where  it  receives  nutri- 
ment; and  (4)  to  the  organs  of  excretion  which  remove  waste  products. 
The  heart  must  efficiently  maintain  circulation,  which  involves  a  sufficient 
minute  volume  output  and  an  adequate  blood  pressure.  The  "  factor  of 
safety  "  or  reserve  force  of  the  heart  is  great.  The  guiding  principle  of 
treatment  is  restoration  of  reserve  force.  The  muscle  power  of  the  heart 
is  the  chief  concern  of  the  therapeutist. 

Harrington  Sainsbury  (*'^)  emphasizes  this  in  a  most  charming  and 
forceful  way  in  the  prologue  to  his  little  volume  "  Principia  Thera- 
peutica,"  in  a  dialogue  between  the  pathologist  and  internist,  parts  of 
which  the  author  was  wont  to  use  in  beginning  his  course  of  lectures  in 
therapeutics. 

Path. :  "  The  apothecary  tells  me  there  is  a  long  bill  on  account, — 
digitalis,  strophanthus,  sparteine,  and  Heaven  knows  what  more,  for  I 
could  not  outstay  the  tale  of  the  remedies  employed.  Friend,  what  had 
you  in  mind,  and  what  was  the  real  task  before  you,  could  you  but  have 
seen?  See  here,  this  aortic  valve,  which  you  rightly  diagnosed  to  be 
narrowed,  it  scarcely  admits  a  thin  pencil — and  the  valves,  if  you  can  call 
them  such,  fused  and  thickened  as  they  are,  and  hard  as  a  piece  of 
Roman  mortar;  they  do  not  look  exactly  amenable  to  treatment;  did  you 
think  to  soften  them?  And  this  heart  muscle,  its  fibers  stretched  and 
degenerate,  what  hope  was  there?  Doubtlesss  you  proposed  to  make  new 
fibers  to  overcome  the  destruction  ?  What  a  commentary  upon  the  drug 
list  is  here  I  " 

Phys. :  "  Not  mine  the  fault,  for,  as  you  say,  I  did  not  spare  the  drugs, 


9o6     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

but  proceed — this  case  of  stenosed  aorta  which  you  have  so  accurately 
described,  was  taken  from  the  body  of  a  woman.  Can  you  favor  me  with 
her  age?  " 

Path. :  "  Seventy-six." 

Phys. :  "  Precisely,  and  her  history  tells,  I  think,  that  though  always 
ailing,  her  symptoms  did  not  point  definitely  to  failing  heart  until  after 
her  sixty-seventh  year.  The  rigid  valves  are  so  thickened  that  the  orifice 
is  reduced  to  a  mere  chink.  Could  you  perhaps  give  a  date  to  this 
calcification?  " 

Path. :  "  That  would  be  difficult ;  it  is  certainly  not  of  yesterday." 

Phys. :  "  The  change  has  clearly  been  of  slow  development,  and  I 
think  you  will  admit  that  its  first  beginnings  may  date  back  many  years, 
perhaps  to  infancy,  and  that  in  this  extreme  form,  it  must  have  existed 
for  many  months." 

Path. :  "  Agreed." 

Phys. :  "  And  yet  symptoms  have  been  so  surprisingly  absent.  But 
you  are  well  aware,  this  is  no  isolated  occurrence,  and  cases  as  extreme 
as  this  have  been  entirely  latent  through  a  long  life,  and  have  proved  com- 
patible even  with  seeming  good  health.  This  was  so  in  a  case  which  I 
have  in  mind,  in  which  the  patient,  also  a  woman,  again  reached  the  age 
of  seventy-six." 

Path. :  "  Need  we  elaborate  this  portion  of  the  argument?  " 

Phys. :  "  Willingly  I  pass  on,  but  first  let  me  very  briefly  insist  upon 
the  inference;  viz.,  that  this  specimen  declares  vitality,  not  mortality. 
Here,  for  instance,  is  a  vital  organ  irreparably  damaged  at  the  fountain- 
head,  so  to  speak,  and  yet  the  patient  outlives  her  three-score  years  and 
ten. 

"  By  what  means?  You  have  called  attention  to  the  dilated  chambers 
of  the  heart  and  to  the  stretched  and  degenerate  fibers  of  the  muscular 
walls;  you  have  confirmed  these  degenerations  by  the  microscope,  and 
you  have  admitted,  I  think,  that  these  same  changes  give  clear  evidence  of 
long  standing,  and  that  some  of  them,  e.g.  the  dilations,  must  reach  back 
in  their  beginnings  to  the  first  changes  in  the  damaged  valve;  thus  you 
have  borne  witness  to  an  inadequacy,  declared,  and  long  prepared.  Not 
by  virtue  of  these,  but  in  their  despite,  has  life  been  prolonged,  and  yet 
the  patient  attains  to  the  age  of  seventy-six.    By  what  means? 

"  Surveying  the  whole  case,  and  placing  upon  the  one  side  the  work  to 
be  done,  the  mass  of  blood  to  be  moved,  the  obstruction  to  be  overcome, 
and  upon  the  other,  available  forces  of  the  heart  muscle,  we  must  confess, 
I  grant  it,  that  the  latter  appear  wholly  unequal  to  the  task.  Yet  the  sum 
of  it  all  is  a  long  life.  Will  you  think  me  unreasonable  if  I  claim  this 
heart  is  an  instance  of  triumph,  not  of  failure?  " 


FACTORS  OF  PROGRESS  IN  THERAPY  907 

Myocardial  insufficiency  arises  from  many  causes.  In  its  chronic 
form  it  is  caused  by :  myocardial  changes  or  lesions ;  lesions  of  the  valves ; 
lesions  affecting  the  vascular  fields  of  the  efferent  arteries;  overexertion; 
poisons,  especially  alcohol  (beer);  adherent  pericardium;  goitre,  and 
Graves'  disease.  Numerous  anatomical  bases  such  as  coronary  sclerosis, 
interstitial  myocarditis,  fragmentation  and  segmentation,  parenchyma- 
tous degeneration,  fatty  or  amyloid  degeneration,  and  lesions  affecting 
the  bundle  of  His  can  be  ascribed  as  the  underlying  cause.  Hypertrophy 
or  dilation,  or  both,  may  exist.  Hypertension,  alone  or  in  combination 
with  nephritis,  is  frequently  associated  with  the  myocardial  insufficiency. 
But  irrespective  of  the  nature  of  the  cause,  or  of  the  lesion,  or  of 
associated  complications,  the  important  desideratum  is  restoration  of 
myocardial  function. 

But  what  are  the  functions  of  the  heart  muscle?  They  depend  on  its 
cardinal  properties,  which  are  five  in  number,  contractility  (inotropism), 
conductivity  (dromotropism),  irritability  (bathmotropism),  rhythmicity 
(chronotropism),  and  tonicity.  Cardiac  function  may  be  disturbed  in 
relation  to  all  or  one  or  a  combination  of  these  properties  recognition  of 
which  markedly  affects  the  efficiency  of  treatment,  since  treatment  can 
be  directed  especially,  in  some  instances,  towards  one  or  more  of  these 
derangements.  Digitalis  in  therapeutic  doses  affects  tonicity,  conduc- 
tivity, and  contractility.  In  toxic  doses  irritability  is  greatly  increased 
and  rhythmicity  markedly  disturbed. 

A  word  might  be  said  concerning  renal  function  in  myocardial  insuf- 
ficiency, since  it  must  be  considered  in  the  treatment  of  this  condition. 

Myocardial  Insufficiency  and  Renal  Function  (""). — Myocardial  in- 
sufficiency may  occur  independently,  but  in  a  large  proportion  of  cases  it 
develops  in  association  with  nephritis.  It  is  often  impossible,  on  purely 
clinical  lines  in  an  individual  case,  to  decide  whether  the  kidney  or  heart 
is  primarily  responsible  for  the  clinical  picture  encountered.  In  this 
connection  renal  functional  studies  are  of  the  greatest  assistance. 

Marked  renal  insufficiency  may  result  from  pure  chronic  passive  con- 
gestion. Very  exceptionally,  clinically  and  experimentally,  the  functional 
studies  reveal  a  decrease  in  function  equaling  that  seen  in  the  most  severe 
grades  of  nephritis.  Since  the  congestion  to  effect  this  must  be  of  a  most 
extreme  grade  death  is  imminent  on  account  of  the  heart.  As  a  rule,  in 
myocardial  insufficiency,  with  a  symptomatic  and  urinary  picture  identical 
with  that  seen  in  a  moderately  advanced  nephritis  alone,  or  in  nephritis 
associated  with  a  cardiac  break,  renal  function  as  indicated  by  both  excre- 
tory and  retention  tests  is  surprisingly  good.  When  low  renal  function  is 
followed  by  an  increased  phthalein  output,  the  amount  of  increase  gives 
a  fair  approximation  of  the  extent  of  cardiac  improvement. 


9o8     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

In  this  connection  also  urea  and  total  non-protein  nitrogen  studies  are 
of  great  value.  In  pure  passive  congestion,  an  increase  in  total  non- 
protein nitrogen  above  50  mg.  to  100  c.c.  of  blood  is  extremely  rare.  In 
only  three  instances  among  several  hundred  cases  studied  has  the  author 
encountered  it.  Foster  has  lately  reported  three  more  instances.  Blood 
creatinine  is  rarely  significantly  increased  in  pure  passive  congestion  of 
the  kidney.  The  finding  of  normal  nitrogen  figures,  therefore,  is  of  con- 
siderable diagnostic  significance.  A  phthalein  rapidly  returning  to 
normal  associated  with  a  low  level  of  blood  total  non-protein  nitrogen 
and  urea  speaks  strongly  for  passive  congestion  as  the  underlying  process. 

Treatment  of  Myocardial  Insufficiency. — Myocardial  insufficiency 
constitutes  a  pathological  indication  for  treatment,  and  calls  for  treat- 
ment notwithstanding  other  conditions  present.  The  principles  under- 
lying this  treatment  are  rest,  limited  diet,  limited  salt  and  fluid  intake, 
depletion  through  bleeding,  purgatives,  diuresis  or  paracentesis,  and  sup- 
port of  the  heart.  In  addition,  certain  symptoms  may  call  for  special 
attention. 

In  many  instances  the  general  treatment  is  more  important  than  drug 
therapy.  On  the  other  hand,  drugs  are  of  unquestionable  value,  fre- 
quently playing  an  important  role.  In  this  article,  detailed  consideration 
can  be  allowed  only  drug  therapy. 

Rest. — This  is  essential  and  must  be  complete  at  first,  absolute  rest 
of  short  duration.  In  long  continued  chronic  myocardial  insufficiency, 
absolute  rest  is  of  course  impossible.  A  back  rest  often  affords  great 
comfort.  An  additional  reason  for  absolute  rest  is  found  in  the  serious 
consequences  which  may  attend  exercise  in  a  patient  under  the  influence 
of  digitalis. 

Diet. — This  must  be  restricted  in  three  ways  as  to  ( i )  the  quantity 
taken  at  one  feeding,  (2)  the  salt  content,  and  (3)  water  intake.  Rest 
for  the  stomach  as  well  as  for  the  heart  must  be  insisted  on.  Do  not 
overfeed.    This  is  a  good  rule,  often  broken. 

Fluids. — The  intake  of  water  and  fluids  should  be  restricted,  the  more 
the  edema,  the  greater  the  restriction.  A  special  fluid  chart,  indicating 
the  fluid  intake  and  the  urinary  output  should  be  kept  in  all  cases  with 
marked  edema.  The  total  fluid  intake  should  be  limited  to  i  to  1.5  liters 
a  day  at  first;  more  fluid  being  allowed  as  diuresis  is  established  and 
edema  disappears.  Enormous  quantities  of  water  may  be  lost  in  the 
course  of  a  few  days,  a  decrease  of  20  to  30  pounds  in  the  course  of 
5  to  6  days  not  being  infrequent.  In  one  of  the  author's  cases,  70  pounds 
were  lost  in  one  week,  anasarca  disappeared,  and  the  phthalein  output 
increased  from  sixteen  per  cent,  to  normal. 

Sodium  Chloride. — Widal  has  shown  how  important  is  the  restriction 


FACTORS  OF  PROGRESS  IN  THERAPY  909 

of  sodium  chloride.  In  the  diet  the  salt  content  must  be  small.  An 
absolutely  salt-free  diet  is  practically  impossible,  and  is  not  necessary. 
It  is  next  to  impossible  to  obtain  a  salt  content  less  than  i  gm.  a  day. 
Milk  contains  0.16  per  cent,  sodium  chloride,  so  that  any  diet  containing 
milk  of  necessity  contains  some  salt. 

So  great  restriction  of  salt  is  often  not  advisable  over  prolonged 
periods.  The  guide  to  the  amount  allowed  is  found  in  the  ability  of  the 
kidney  to  excrete  it.  Where  fair  amounts  are  excreted,  and  particularly 
where  its  concentration  in  the  urine  is  good,  more  can  be  allowed.  Many 
patients  are  kept  on  a  salt-free  diet  long  after  the  necessity  of  it  has 
passed.  Great  quantities  of  salt  are  excreted  as  a  rule  with  the  clearing 
up  of  edema  and  anasarca.  Prolonged  use  of  salt-free  diet  may  lead  to 
deprivation  of  the  tissues  of  sodium  chloride. 

Methods -of  Depletion. — Bleeding,  tapping  of  the  pleural,  pericardial, 
or  abdominal  cavities,  diuresis  and  purgation,  may  all  be  indicated  at 
times.  Sweating  is  contraindicated  owing  to  the  strain  involved  upon 
the  heart. 

Bleeding. — Venesection  is  indicated  in  acute  dilation  of  the  heart, 
particularly  of  the  right  heart. 

Purgation. — This  is  employed  in  practically  all  cases  of  outspoken 
myocardial  insufficiency.  It  is  useful  for  the  removal  of  water,  for  the 
removal  of  putrefactive  material  from  the  intestine,  and  also  for  the 
relief  of  intestinal  distention.  It  may  be  employed  without  fear  even 
where  asthenia  is  marked  and  the  pulse  feeble.  Hydragogues  should  be 
used.  Magnesium  sulphate  16  to  48  grams  (>4  to  i>^  ounces)  given  in 
concentrated  form  each  morning  on  an  empty  stomach  is  the  most  satis- 
factory method  of  inducing  purgation  in  the  majority  of  cases.  This 
usually  results  in  two  or  three  large  fluid  stools  each  day.  When  this 
is  not  well  borne  by  the  stomach,  i.e.  when  it  occasions  nausea  and  vomit- 
ing, I  or  2  compound  cathartic  pills  each  night  or  compound  jalap 
powder  i  to  3  gms.  ( 15  to  40  grains)  or  compound  elaterin  powder  3  to  6 
gms.  (1/20  to  i/io  grain)  in  alcohol  is  sometimes  efficacious  when 
other  methods  have  failed.     Enemata  may  occasionally  be  necessary. 

After  the  anasarca  disappears,  milder  purgatives  or  laxatives  such  as 
cascara  and  liquorice  powder  may  be  required  for  regulating  the 
intestines. 

Diuresis. — This  is  usually  obtained  through  the  use  of  digitalis. 
Where  this  is  not  effectual,  recourse  is  had  to  one  of  the  caffeine  diuretics. 
Theocine  is  most  satisfactory,  0.2  gm.  (3  grains)  t.i.d.  for  one  day.  The 
effect  is  noted  and  the  drug  repeated  on  alternate  days  if  necessary. 

Support  of  Heart. — Digitalis  is  the  drug  par  excellence  in  this  con- 
nection.    Introduced  by  Withering  in  17^5  for  the  relief  of  dropsy,  it 


9IO     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

has  become  our  mainstay  in  the  treatment  of  myocardial  insufficiency. 
Its  relation  to  circulatory  disturbances  was  emphasized  by  John  Ferrier, 
1799.  Although  a  great  amount  of  work  has  been  done  on  this  subject, 
little  is  yet  known  in  a  practical  way  concerning  the  chemistry  of  the 
active  principles  of  digitalis.  Undoubtedly,  the  future  will  furnish  syn- 
thetic chemicals  which  ultimately  will  replace  digitalis.  But  in  the  mean- 
time, striking  results  can  be  obtained  through  its  intelligent  use. 

Myocardial  insufficiency  constitutes  the  indication  for  its  use  regard- 
less of  the  nature  of  the  underlying  lesions.  Auricular  fibrillation 
demands  an  intensive  digitalis  therapy,  and  indeed  it  is  in  cases  of 
auricular  fibrillation  that  we  see  its  most  striking  effects.  Its  best  diuretic 
effect  is  seen  in  dropsy  dependent  upon  circulatory  changes  in  the  kidneys. 
In  the  acute  myocardial  involvement  of  acute  febrile  diseases,  the  useful- 
ness of  digitalis  is  rather  limited.  Once  circulatory  collapse  supervenes, 
results  are  meager.  Earlier  in  the  disease,  before  blood  pressure  is 
markedly  depressed,  good  results  can  be  obtained  especially  in  cases 
developing  fibrillation.  Toxic  manifestation  should  be  carefully  watched 
for  in  such  conditions. 

Digitalis  is  manifold  in  its  action.  It  acts  on  the  heart  muscle* 
itself,  increasing  its  irritability,  tonicity,  and  strength  of  contraction;  on 
the  bundle  of  His,  decreasing  conductivity;  on  the  vagus,  slowing  the 
rate;  on  the  vascular  system  through  the  vasomotor  center;  and 
directly  on  the  vessel  walls  inducing  vasoconstriction  and  increase  in 
blood  pressure.  It  slows  the  heart,  increasing  its  force  and  the  output  per 
beat,  and  per  minute,  and  tends,  in  passive  congestion  resulting  from  myo- 
cardial insufficiency,  to  shift  the  blood  from  the  venous  side,  where  it  has 
collected,  to  the  arterial  side  of  the  vascular  system.  In  therapeutic  doses 
it  results  in  improved  circulation  through  the  kidney  (a  relative  vaso- 
dilating effect  upon  the  renal  vessels  being  claimed),  diuresis  resulting. 
It  finds  its  greatest  value  in  cases  of  mitral  disease  with  marked  edema 
and  small,  rapid,  and  irregular  pulse,  although  it  is  of  value  in  all  cases 
of  myocardial  insufficiency  despite  the  nature  of  valvular  lesion. 

Digitalis  should  be  administered  in  courses  and  its  use  should  be 
intensive  from  the  beginning,  irrespective  of  the  preparation  used.  A 
single  course  may  suffice,  but  repeated  courses  are  usually  indicated.  In 
auricular  fibrillation  intensive  treatment  is  indicated  at  first  and  subse- 
quently, after  compensation  is  reestablished,  more  or  less  continuous  or 

*  In  this  connection  the  work  of  Schliomensun  is  extremely  illuminating.  (Arch, 
f.  Path.  u.  Phann.,  LXIII.)  An  alcoholic  phosphatid  was  extracted  from  the  hearts 
of  animals  receiving  digitalis  therapy,  which  when  injected  into  a  second  animal  pro- 
duced all  of  the  biological  reactions  of  digitalis.  This,  he  claims,  indicates  a  direct 
combination  of  digitalis  with  the  heart  muscle.  Similar  extracts  from  other  tissues 
of  these  animals  failed  to  yield  such  a  product,  indicating  that  the  substance  was 
specific  to  heart  muscle. 


FACTORS  OF  PROGRESS  IN  THERAPY  911 

tonic  treatment.  In  this  condition  small  doses  can  be  taken  almost  con- 
tinually, or  at  frequent  intervals  for  months  or  years.  Patients  may  feel 
well  on  this  regimen,  who  otherwise  do  badly. 

The  preparations  of  digitalis  are  numerous,  but  four  stand  out  pre- 
eminently. These  are  the  powdered  leaf,  the  tincture,  the  infusion,  and 
digipuratum.  Each  preparation  has  its  advocates.  Results  can  be  ob- 
tained with  any  of  them  provided  the  preparation  is  an  active  one  and 
that  it  is  properly  administered  to  suitable  cases. 

The  preparations  most  commonly  used  in  the  wards  of  our  hospital 
are  the  infusion  and  the  tincture.  The  infusion  is  given  fevery  3  or  4 
hours  for  48  hours.  The  infusion  is  an  aqueous  extract  and  contains 
relatively  more  digitonin  than  the  tincture.  As  a  diuretic  it  is  particularly 
valuable.  It  should  be  prepared  fresh,  a  new  supply  being  obtained  once 
a  week.  The  tincture  is  also  excellent.  It  is  an  alcoholic  preparation, 
containing  relatively  more  digitoxin,  digitalin,  and  digitophyllin  than  the 
infusion.  It  is  administered  in  i  c.c.  doses  every  3  or  4  hours  for  48 
hours.  It  is  usually  combined  with  tincture  amygdali  amari  or  some 
other  bitter  and  administered  well  diluted. 

The  powdered  leaf  is  given  in  0.065  to  o.i  gm.  (i  to  i^  gr.)  doses 
every  3  or  4  hours  for  48  hours.  Digipuratum  is  a  standardized  prepa- 
ration of  digitalis  in  tablet  form  each  corresponding  to  0.065  to  o.  i  gm. 
(i  to  13^  gr.)  of  the  digitalis  leaf.  Four  tablets  are  given  during  the  first 
24  hours,  three  the  second,  two  the  third,  and  one  the  fourth.  It  is  an 
active  preparation  and  well  standardized,  but  much  more  expensive  than 
any  of  the  foregoing  preparations  which  are  equally  efficacious,  provided 
they  are  properly  standardized.  Digipuratum  is  also  marketed  in 
ampules  in  liquid  form.  This  preparation  can  be  given  intravenously  or 
intramuscularly  without  marked  irritation.  The  ampule  contains  i  c.c. 
which  corresponds  to  o.  i  gm.  of  the  leaf. 

The  doses  given  above  represent  the  routine  of  the  hospital.  It 
cannot  be  too  strongly  emphasized,  however,  that  digitalis  should  not  be 
measured  in  grams,  grains,  or  hours,  but  by  results.  The  chief  requisites 
are  an  active  standardized  preparation  and  proper  indications.  The 
former  is  readily  obtained  and  is  unquestionably  of  the  greatest 
importance. 

Standardization  of  Digitalis. — Two  methods  are  in  common  use, 
the  frog  and  the  cat  method.  The  frog  method  consists  of  injecting  the 
digitalis  preparation  into  the  anterior  lymph  sac  of  a  frog  (Rana  pipiens) 
and  determining  the  amount  necessary  to  bring  about  systolic  standstill  in 
one  hour.  The  results  are  expressed  in  heart  tonic  units.  This  conveys 
no  impression  as  to  the  activity  of  the  preparation  unless  one  knows  what 
constitutes  a  heart  tonic  unit.    According  to  Houghton,  a  heart  tonic  unit 


912     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

is  ten  times  the  normal  fatal  dose  per  gram  of  frog;  to  Edmonds  it  is 
the  amount  per  20  gm.  weight  of  frog  necessary  to  bring  about  systolic 
standstill  in  one  hour,  while  according  to  Hale,  it  is  the  amount  necessary 
per  gm.  of  body  weight.  A  heart  tonic  unit  may  therefore  vary 
400  per  cent,  according  to  what  constitutes  the  standard.  Neverthe- 
less, the  standardization  is  of  value  if  one  accepts  any  standardized 
preparation  and  learns  how  to  use  it  intelligently.  The  frog  method 
is  not  satisfactory  for  the  standardization  of  a  dilute  preparation,  such 
as  the  official  infusion,  since  such  large  quantities  must  be  introduced 
into  the  lymph  sac  that  absorption  is  often  not  complete  at  the  end  of 
an  hour. 

The  cat  method  of  Hatcher  C^)  is  simple  and  satisfactory.  The 
preparation  to  be  tested  is  slowly  run  into  the  femoral  vein  of  a  cat  until 
death  results.  The  number  of  c.c.  per  kg.  of  cat  constitutes  a  cat  unit. 
The  technic  as  employed  by  the  author  in  standardizing  the  infusion  is  as 
follows : — the  cat  is  given  just  sufficient  ether  to  permit  a  cannula  being 
placed  in  the  femoral  vein.  By  means  of  a  burette  or  a  syringe  10  c.c.  of 
the  filtered  infusion  is  injected  in  the  course  of  five  minutes,  and  i  c.c. 
every  two  minutes  thereafter  until  death.  The  total  amount  is  noted,  and 
the  amount  per  kg.  of  the  cat  unit  is  calculated. 

The  following  emphasizes  the  importance  of  standardization.  Leaves 
from  various  sources  (German,  English,  and  American)  obtained  for  the 
hospital  pharmacy  infusions  were  prepared  according  to  the  United 
States  Pharmacopoeia.  Macht  C*)  and  the  writer  found  that  some  of 
these  infusions  required  only  6  to  7  c.c.  per  kg.,  whereas  others  required 
10  and  12,  and  one  (the  German  leaf)  required  23  c.c.  per  kg.  to  kill  the 
cat.  A  variation  of  400  per  cent,  was  therefore  found  in  leaves  in  the 
hospital  pharmacy.  Before  leaving  Baltimore,  the  writer  introduced 
American  grown  digitalis  (Wisconsin  leaf)  into  general  use  in  the 
wards.  Standardized  American  grown  digitalis  (Minnesota,  Washing- 
ton, and  Oregon)  was  used  extensively  by  the  Medical  Corps  of  the 
Army. 

Eggleston  (®^)  has  recently  claimed  that  0.143  cat  units  per  pound  of 
body  weight  constitutes  the  amount  necessary  for  maximal  therapeutic 
effects.  The  additional  claim  is  also  made  that  this  full  amount  can  be 
given  in  24  rather  than  in  48  hours,  one-half  being  given  in  the  first  dose, 
one-third  4  to  6  hours  later,  and  small  doses  at  4-hour  intervals  until  the 
calculated  amount  is  reached.  Doses  up  to  50  c.c.  of  the  infusion  now 
in  use  in  our  wards  have  been  given  as  the  initial  dose  without  untoward 
effect.  This  method  has  been  thoroughly  tested  in  my  wards  during  the 
last  three  years  by  Drs.  White  and  Morris  C^)  utilizing  standardized 
American  grown  digitalis. 


FACTORS  OF  PROGRESS  IN  THERAPY  913 

"  Our  impression  is  that  the  Eggleston  method  is  a  valuable  addition 
in  digitalis  therapy,  that  it  gives  confidence  in  the  use  of  the  drug,  and 
that  the  shorter  time  necessary  for  securing  digitalis  effects  should  give 
the  method  wide  use.  Results  are  frequently  obtained  within  twenty- 
four  hours. 

The  method  must  be  used  with  care  to  select  cases  in  which  these 
effects  are  desired.  Cases  of  acute  or  chronic  infections,  with  the  proba- 
bility of  the  presence  of  endocardial  infections,  should  be  given  the 
method,  if  at  all,  only  after  careful  study,  because  of  the  possibility  of 
embolism  and,  quite  as  important,  in  our  opinion,  the  possibility  of 
associated  myocardial  changes  predisposing  to  block." 

The  method  requires  careful  study  of  the  patient  before,  during,  and 
after  its  administration,  and  since  it  produces  powerful  and  clear-cut 
effects,  should  be  used  with  extreme  care  and  judgment.  The  digitalis 
effect  is  often  secured  within  24  hours. 

Since  there  are  so  great  variations  in  the  potency  of  digitalis,  it 
becomes  imperative  for  its  intelligent  use  that  the  physician  be  familiar 
with  the  potency  of  the  preparation  which  he  is  administering.  The  only 
other  alternative  is  to  push  the  drug  until  the  therapeutic  effect  is 
obtained,  provided  it  is  a  case  suitable  to  digitalis  therapy. 

In  order  to  do  this,  one  must  have  well  in  mind  what  constitutes  the 
therapeutic  stage  of  digitalis  treatment,  and  what  criteria  are  to  be 
accepted  as  indicating  the  desired  digitalis  effect.  Slowing  of  the  pulse 
is  sometimes  erroneously  accepted  as  the  criterion.  It  should  not  be, 
since  slowing  of  the  pulse  does  not  always  occur  in  the  therapeutic  stage, 
and  since  slowing  of  the  pulse  is  not  attained  by  digitalis  in  certain  types 
of  myocardial  insufficiency.  Thus  Edens  (")  states  that  slowing  does 
not  occur  when  hyperthyroidism  is  present,  in  acute  myocarditis,  in 
idiopathic  hypertrophy,  or  in  the  small  heart  of  tuberculous  diathesis. 
In   such   conditions   the   toxic   manifestations    appear   before    slowing 

occurs. 

When  the  patient  is  closely  followed,  the  therapeutic  stage  is  often 
accompanied  by  the  first  toxic  manifestations,  which  are  usually  readily 
recognized.  The  following  should  be  closely  observed:  (i)  the  urinary 
output  in  relation  to  the  intake,  since  diuresis  usually  characterizes 
the  therapeutic  stage  and  oliguria  the  toxic  stage  of  digitalis;  (2)  the 
outline  of  the  heart;  (3)  the  character  of  the  heart  beat  and  heart  sounds ; 
(4)  the  symptomatic  condition  of  the  patient  with  respect  to  dyspnea, 
cyanosis,  and  edema;  (5)  the  effect  on  blood  pressure  and  on  the  char- 
acter of  the  pulse;  and  (6)  the  effect  on  cardiac  function  as  revealed  in 
electrocardiograms  the  inversion  of  the  T  wave  occurs  in  the  thera- 
peutic stage,  but  block  and  other  arrythmias  indicate  toxicity. 


914     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

The  time  element  in  digitalis  therapy  is  important.  It  is  unusual  to 
get  digitalis  effects  from  any  preparation  given  by  mouth  in  the  ordinary 
dosage  in  less  than  36  to  48  hours,  more  frequently  48  to  72  hours. 
Digitalis  given  today  does  not  manifest  its  action  until  the  day  after 
tomorrow.  Where  immediate  effect  is  necessary  recourse  may  be  had 
to  strophanthin,  and  where  the  need  is  less  urgent,  Eggleston's  dosage 
may  be  employed,  provided  the  case  is  otherwise  suitable. 

Digitalis  is  cumulative  in  its  effects  and  consequently  should  be  given 
in  courses.  When  the  desired  amount  is  prescribed,  the  digitalis  should 
be  stopped  and  the  effect  noted.  The  toxic  effects  are  nausea  and  vomit- 
ing, vertigo,  syncope,  and  diminished  urinary  secretion.  The  pulse  may 
become  either  slow  (vagus  effect)  or  fast  (increased  muscle  irritability). 
Irregularities  may  develop;  a  bigeminal  or  trigeminal  pulse  is  rather 
pathognomonic  of  the  toxic  state.  Auricular  fibrillation  may  develop. 
Sudden  cumulative  effects  are  said  to  occur,  but  the  more  closely  a 
patient  is  watched,  the  less  sudden  as  a  rule  are  the  toxic  effects  of 
digitalis.  Nausea  and  vomiting,  which  herald  toxic  action,  often  go 
unheeded. 

The  effect  on  blood  pressure  is  deserving  of  comment,  since  digitalis 
in  animal  experiments  leads  to  increase  in  blood  pressure.  Little  or  no 
influence  on  blood  pressure  is  seen  clinically.  In  some  cases  a  rise  is 
encountered,  but  more  frequently  a  gradual  fall  in  pressure  is  seen,  which 
is  often  synchronous  with  unquestionable  clinical  improvement.  Natu- 
rally rest,  diet,  purgation,  and  depletion  also  play  a  role  in  determining 
the  effect  on  blood  pressure. 

Substitutes  for  Digitalis. — For  routine  use  no  drug  can  replace  digi- 
talis. Strophanthin,  however,  is  unquestionably  the  best  substitute,  and 
in  certain  conditions  it  is  preferable.  Strophanthin  is  the  most  valuable 
preparation,  the  tincture  of  strophanthus  comparing  in  no  way  with  the 
tincture  of  digitalis. 

Strophanthin  is  given  in  0.25  to  0.5  mgm.  doses  intravenously  and  in 
0.25  to  I  mgm,  doses  intramuscularly.  Local  massage  for  15  minutes  at 
the  point  of  injection  obviates  the  local  irritant  effect  otherwise  encoun- 
tered. When  used  in  i  mgm.  doses,  it  cannot  be  repeated  within  24 
hours;  a  dose  of  0.5  mgm.  may  be  repeated  in  12  hours,  although  in  the 
majority  of  cases  it  is  unnecessary.  Doses  of  0.25  mgm.  should  be 
repeated  in  8  to  12  hours.  Strophanthin  is  given  as  is  digitalis  in  courses 
of  2  to  3  days'  duration. 

Warning  is  necessary  concerning  its  use  where  digitalis  has  been 
already  administered.  As  already  stated,  digitalis  requires  24  to  36 
hours  to  demonstrate  its  effect.  The  addition  of  0.5  mgm.  strophanthin 
at  the  end  of  a  course  of  digitalis  may  precipitate  alarming  toxic  mani- 


FACTORS  OF  PROGRESS  IN  THERAPY  915 

festations.  On  the  other  hand,  strophanthin  is  admirable  when  used  in 
the  beginning  of  a  course  of  digitalis  as  follows;  a  patient  suffering  from 
acute  dilatation  of  the  right  heart  may  be  bled.  0.5  mgm.  strophanthin 
given  intramuscularly,  and  then  a  course  of  digitalis  started  in  the  ordi- 
nary way.  From  this  procedure  an  almost  immediate  digitalis  effect  is 
secured  and  maintained. 

Strophanthin  acts  pharmacologically  and  therapeutically  much  as 
digitalis,  but  has  somewhat  less  effect  in  vasoconstriction.  It  constricts 
the  splanchnic  terminals,  as  does  digitalis,  but  not  the  vessels  of  the 
extremities  and  cerebrum,  which  may  even  undergo  slight  dilatation  at 
times.  Considerable  controversy  has  been  waged  over  its  effect  upon 
the  coronaries.  Digitalis  constricts  the  coronaries  and,  therefore, 
decreases  the  blood  supply  to  the  heart  muscle.  Loeb  claims  that  stro- 
phanthin here  exerts  a  dilating  influence.  Voegtlin  and  Macht  using 
arterial  rings  find  a  constricting  influence  for  digitalis  and  a  dilating 
effect  for  strophanthin.  The  chief  effect  of  both  drugs  is  identical,  how- 
ever; in  shifting  the  blood  from  the  venous  to  the  arterial  side  of  the 
vascular  system. 

The  time  necessary  for  the  manifestation  of  their  physiological  effect 
is  the  chief  point  of  difference.  The  strophanthin  effect  is  almost  imme- 
diate, whereas  digitalis  requires  24  to  36  hours.  Strophanthin  is,  there- 
fore, used  in  preference  to  digitalis  where  the  need  is  urgent. 

Caffeine  or  some  member  of  the  caffeine  group  is  sometimes  sub- 
stituted for  digitalis  where  the  latter  fails.  When  slowing  results  from 
its  use,  the  pharmacological  effect  resembles  that  of  digitalis.  However, 
the  pulse  rate  is  more  frequently  accelerated  than  retarded.  Unfortu- 
nately, its  use  is  commonly  attended  with  the  development  of  palpitation, 
msomnia,  and  sometimes  nausea,  vomiting,  and  delirium.  These  un- 
toward effects  often  appear  as  early  as  the  effect  on  the  heart,  conse- 
quently caffeine  is  seldom  employed  in  this  connection. 

But  these  purin  derivatives  are  excellent  diuretics.  According  to 
Schroeder,  they  exert  a  specific  effect  on  the  cells  of  the  renal  tubules 
and  consequently  they  are  often  employed  in  myocardial  insufficiency  not 
as  a  substitute  for  digitalis,  but  as  a  synergist  from  the  point  of  view 
of  renal  secretion.  Theobromine  has  a  more  constant  renal  effect  than 
caffeine,  and  is  frequently  used  in  0.7  to  0.5  gm.  t.i.d.,  or  in  the  form  of 
sodio-salicylate  of  theobromine  i  gm.  t.i.d.  The  most  valuable  prepa- 
ration of  the  caffeine  group,  however,  is  theocin,  which  is  administered 
in  0.2  gm.  (3  grain)  doses  three  times  a  day  for  one  day.  It  exerts 
less  cerebral  effect  and  consequently  does  not  result  so  frequently  in 
insomnia.  It  can  be  repeated  on  alternate  days  if  its  effect  disappears 
rapidly.    Where  the  diuretic  effect  of  digitalis  is  lacking,  our  own  prac- 


9i6     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

tice  is  to  turn  to  theocin,  which  is  given  in  addition  to  digitaHs  and  in 
the  manner  just  indicated. 

Certain  other  remedies  sometimes  substituted  are  perhaps  worthy  of 
mention.  Squill  is  of  value  at  times.  It  has  a  very  mild  digitalis  effect, 
and  is  an  excellent  diuretic.  It  is  given  as  the  tincture  (0.3  to  i  c.c.)  or 
as  the  syrup  (2  to  4  c.c).  Neimeyer's  or  Addison's  pills  which  contain 
one  grain  each  of  calomel,  digitalis,  and  squill  is  a  valuable  preparation. 
Apocynum  as  the  fluid  extract  (i  c.c),  convallaria  as  the  tincture  (0.3 
to  I  c.c),  and  adonidin  10  to  20  mgm.  are  occasionally  used,  but  are  of 
very  doubtful  therapeutic  value.  Spartein  sulphate  0.065  to  0.13  gm.  is 
rarely  employed.  Cactus  grandiflorus  is  absolutely  inert  and  should  be 
deleted  from  the  pharmacopeia. 

Adjuncts  to  Digitalis  Therapy. — Anemia  is  not  at  all  infrequent  in 
myocardial  insufficiency.  Iron  and  arsenic  are  here  of  the  greatest  value. 
Strychnia  is  occasionally  of  value.  Alcohol  in  small  doses  for  its  psychi- 
cal effect  is  employed  at  times,  in  those  accustomed  to  its  use,  when  crav- 
ing is  great. 

The  value  of  charts,  quickly  conveying  the  effect  or  need  of  treat- 
ment from  the  standpoint  of  the  kidney  is  worthy  of  emphasis.  At  a 
glance,  one  accustomed  to  their  use  grasps  the  condition  of  renal 
activity. 

The  Symptomatic  Treatment  of  Myocardial  Insufficiency 

At  times  certain  symptoms  become  so  pronounced  as  to  call  for  special 
treatment  in  addition  to  the  general  treatment  described  above. 

(i)  Edema  is  usually  controlled  by  rest,  diet,  restriction  of  fluids 
and  salts  and  by  digitalis  alone,  or  together  with  one  of  the  caffeine 
bodies.  Where  these  fail,  or  where  the  anasarca  is  extreme  so  that 
pressure  interferes  with  the  action  of  the  heart  or  lungs,  tapping  of  the 
cavities  concerned  is  necessary.  Where  edema  of  the  extremities 
is  so  severe  as  to  threaten  gangrene,  drainage  may  be  employed  with 
success, 

(2)  Dyspnea. — The  cause  of  the  dyspnea  should  be  determined. 
If  mechanical,  paracentesis  may  be  indicated  or  special  attention  to  diet 
if  there  is  pressure  from  intestines  filled  with  gas.  The  back  rest  may 
bring  great  relief.  For  orthopnea,  morphine  10  mgm.  and  atropine  0.5 
mgm.  often  brings  relief.  When  these  fail,  and  when  marked  dilatation 
of  the  right  heart  is  found,  venesection  and  strophanthin  answer  best. 

Formerly  nitrites  were  much  used  in  dyspnea  associated  with  hyper- 
tension. The  dyspnea  is  now  considered  as  evidence  of  beginning  myo- 
cardial weakness  and  calls  for  digitalis  and  not  for  vasodilators. 

(3)  Arrhythmias. — Digitalis  has  a  marked  effect  on  rhythm.    This 


FACTORS  OF  PROGRESS  IN  THERAPY  917 

must  be  constantly  in  mind  since  many  arrhythmias  encountered  cHnically 
are  of  digitaHs  origin,  and  the  treatment  consists  in  the  removal,  not  in 
the  administration  of  the  drug. 

Auricular  fibrillation  is  the  condition  in  which  digitalis  produces  its 
most  brilliant  effects.  "  The  overstretched  auricular  muscles  are  unable 
to  make  concerted  contractions  and  instead  enter  into  a  state  of  tremula- 
tion  or  fibrillation."  These  irregular  impulses  are  transmitted  to  the 
ventricle,  producing  a  confusion  of  rhythm,  or  absolute  irregularity.  The 
output  of  the  heart  is  markedly  decreased,  and  its  efforts  ineffective. 
The  main  effect  of  digitalis  is  lessened  conductivity,  but  an  influence 
is  also  exerted  on  the  irritability  of  the  muscle.  Improvement  in 
rhythm  is  often  accompanied  by  prompt  and  decided  increase  in  blood 
flow. 

Digitalis  is  indicated  in  auricular  flutter.  Fibrillation  is  frequently 
induced  which  disappears  on  the  removal  of  digitalis,  leaving  a  normal 
rhythm  in  its  stead.  Partial  heart  block  is  exaggerated  by  digitalis  which 
intensifies  the  degree  of  the  block  and  tends  to  result  in  a  complete  block. 
Unless  digitalis  is  needed  for  other  reasons,  it  should  be  withheld.  Atro- 
pine, on  the  other  hand,  may  be  effective  in  the  removal  of  this  form  of 
block.  Since  in  complete  heart  block  interference  with  conductivity  is 
sufficiently  complete  to  effect  total  dissociation  in  auricular  and  ventric- 
ular rhythm,  digitalis  can  do  no  harm.  It  renders  ventricular  contraction 
more  effective  and  tends  somewhat  to  decrease  its  rate  and  consequently 
is  of  value.  Extra-systoles  are  the  result  of  increased  myocardial  irrita- 
bility and  hence  tend  to  be  increased  rather  than  decreased  by  the  drug. 
Digitalis,  if  indicated,  can  be  used  effectively  despite  their  existence. 
Extra-systoles  should  be  treated  by  general  hygienic  measures.  Sinus 
arrhythmia  likewise  is  exaggerated  by  digitalis  because  of  the  stimu- 
lation of  the  vagus. 

(4)  Hypertension. — This  is  best  met  through  general  measures  such 
as  rest,  sleep,  diet,  and  depletion.  The  medicinal  lowering  of  blood 
pressure  is  best  effected  through  the  use  of  digitalis.  Other  vaso- 
dilators and  blood  pressure  lowering  drugs  are  rarely  indicated.  The 
use  of  nitrites  should  be  restricted  to  conditions  in  which  there  is  localized 
arteriosclerosis  or  arterial  spasm  in  a  vital  part  as  in  angina  pectoris,  and 
to  cases  in  which,  as  a  result  of  high  blood  pressure,  a  vascular  accident 
such  as  apoplexy  is  feared.  It  must  be  admitted,  however,  that  nitrites 
occasionally  result  in  benefit  when  used  in  conjunction  with  digitalis,  and 
when  digitalis  along  with  general  measures  have  failed.  If  used  at  all, 
the  onset  and  duration  of  their  action  should  be  borne  in  mind.  The 
results  of  Wallace  and  Ringer  {^^)  in  relation  to  these  desiderata  are 
shown  in  the  following  tables: 


9i8     THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 


Drug 

Dose 

Time 
of  be- 

Time 
of   max. 

Duration 
of  action 

Max. 
extent 

Maximum 
extent  of 

ginning 
action 

effect 

{min.) 

action 

action 
(mm.  Hg.) 

I 

Amyl   nitrite 

3  min. 

I 

3 

7 

IS 

Nitroglycerin,   i  per 

In 

cent.  sol. 

I  1/2  min. 

2 

8 

30 

15 

normal 

Sodium  nitrite 

r  gr. 

10 

25 

60 

14 

subjects 

Erythrol  tetranitrate 

1/2  gr. 

15 

2,2 

120-240 

16 

II 

Nitroglycerin 

1/30  gr. 

2 

8 

35 

32 

In 

Sodium   nitrite 

2  gr. 

15 

45 

120 

53 

arterio- 

Erythrol tetranitrate 

2  gr. 

30 

60 

180 

60 

sclerosis 

(5)  Palpitation  and  Cardiac  Distress. — Occasionally  the  gastro- 
intestinal tract  is  at  fault,  and  its  responsibility  should  be  investigated. 
Local  treatment  may  suffice.  The  ice  bag  is  frequently  the  most  potent 
source  of  comfort.  Small  blisters  and  belladonna  plasters  are  of  value 
at  times.  Internally,  potassium  iodide  is  frequently  employed  with  suc- 
cess.   Tincture  aconite  may  also  help  at  times. 

(6)  Gastric  Symptoms. — Nausea  and  vomiting  are  commonly 
encountered.  They  frequently  yield  rapidly  to  the  general  treatment 
already  described.  Their  origin  must  always  be  determined  since  their 
appearance  after  instituting  digitalis  therapy  should  suggest  the  possi- 
bility of  responsibility  of  digitalis.  The  treatment  may  be  withdrawal  of 
digitalis.     Similarly  Epsom  salts  may  be  responsible. 

All  food  should  be  stopped  for  12  hours  if  nausea  and  vomiting 
become  extreme,  and  nothing  should  be  allowed  by  mouth  except  crushed 
ice.  Later,  milk  and  lime  water  are  allowed  in  small  amounts.  Gastric 
sedatives  such  as  sips  of  cold  effervescing  drinks,  champagne,  apollinaris 
water  or  an  ordinary  syphon  are  often  of  value.  Bismuth  i  to  2  grams, 
creosote  o.i  c.c,  dilute  hydrocyanic  acid  0.065  c.c,  cocain  hydrochloride 
5  to  10  mgm.  or  a  mixture  of  tr.  nux  vomica  0.3  c.c.  and  soda  bicar- 
bonate 0.1  gram  may  be  tried.  Counter-irritation  in  the  form  of  a 
mustard  plaster  to  the  abdominal  wall  is  occasionally  helpful. 

Naturally  in  myocardial  insufficiency  associated  with  chronic 
nephritis,  nausea  and  vomiting  may  be  evidences  of  uremia.  All  of  the 
above  methods  may  be  tried  without  success  while  some  general  sedative 
acting  centrally,  such  as  chloral  0.3  gram  every  4  hours  or  morphine  10 
mgm.,  may  bring  relief.  Persistent  nausea  and  vomiting,  particularly  if 
associated  with  a  markedly  enlarged  and  pulsating  liver,  is  an  extremely 
serious  complication,  often  ending  fatally. 


WHAT  IS  NEEDED  TO  ADVANCE  THERAPY    919 

(7)  Cough. — The  cough  is  usually  due  to  circulatory  changes  in 
the  lungs  and  responds  to  the  cardiac  treatment.  Expectorants  are  as  a 
rule  contraindicated. 

(8)  Hemoptysis. — Though  most  alarming  to  the  patient,  hemoptysis 
in  myocardial  insufficiency  is  seldom  serious.  The  patient  should  be 
assured  that  the  hemorrhage  is  salutary  and  does  away  with  the  necessity 
of  doing  a  venesection.  Assurance,  absolute  quiet,  and  an  ice  bag  over 
the  chest  usually  suffice.  When  the  patient  is  markedly  upset,  a  small 
dose  of  morphia  is  often  desirable. 

(9)  Edema  of  the  Lungs. — This  is  an  extremely  serious  complica- 
tion and  calls  for  quick  action.  The  patient  should  be  bled  400  to  600 
c.c.  Morphia  15  mgm.  should  be  given  hypodermically.  Atropin  0.5 
mgm.  is  used  at  times,  but  morphine  is  of  greater  value. 

(10)  Insomnia. — This  is  frequently  a  very  troublesome  symptom. 
A  good  back  rest  with  side  supports  often  allows  a  comfortable  sleep  in 
a  sitting  posture.  Any  of  the  following  hypnotics  or  sedatives  can  be 
tried — paraldehyde  2  to  8  c.c.  in  capsules,  sulphonal  0.6  to  2  gms., 
Hoffman's  anodyne  2  to  4  c.c,  spts.  of  chloroform  0.3  to  0.6  c.c,  spts. 
of  camphor  i  to  3  c.c.  alone  or  2  c.c.  in  combination  with  ether  2  c.c, 
veronal  0.3  gm.,  barbital  or  barbital  sodium  0.6  to  i  gm.  or  urethane 
I  to  2  gm.  Where  these  do  not  give  relief  it  is  better  not  to  waste 
valuable  time.  Morphia  10  to  15  mgm.  alone  or  in  combination  with 
atropine  0.5  mgm.  should  be  given  hypodermically. 

In  these  various  ways  conditions  arising  from  myocardial  insufficiency 
are  met.  The  means  used  are  successful  in  so  far  as  they  influence  func- 
tion. They  can  have  little  if  any  effect  on  structure.  They  do  in  many 
cases  so  modify  function  that  discomfort  is  converted  into  comfort, 
dangerous  crises  averted,  and  life  prolonged  with  a  reasonable  degree  of 
daily  activity. 

(8)    Medical  Organization 

Specialization  more  than  any  other  single  factor  serves  to  advance  a 
science.  A  coterie  of  workers  devoting  "  whole  time  "  to  the  advance- 
ment of  a  subject  brings  to  it  that  concerted  continuous  thought  and 
effort  so  necessary  for  success.  The  field  of  pharmacology  is  being  tilled 
and  cultivated  by  an  ever-increasing  group.  Chairs  of  pharmacology 
assure  the  development  of  this  subject.  Similiarly,  institutions  such  as 
the  Speyer  House  and  the  Rockefeller  Institute  and  Hospital  have  con- 
tributed greatly  to  progress.  The  methods  adopted  by  Ehrlich,  Flexner, 
and  Cole  in  relation  to  trypanosomiasis,  syphilis,  relapsing  fever,  menin- 
gitis, poliomyelitis,  and  pneumonia  are  those  most  needed  in  medicine. 
Cole  and  his  co-workers  have  exercised  the  type  of  critical  judgment  and 


920     THE  PHARMACOLOGICAL  BASTS  OF  MEDICINE 

employed  the  numerous  controls  so  necessary  for  sound  progress  yet  so 
uniformly  lacking  in  most  therapeutic  investigation. 

Pharmacological  societies  and  publications,  the  natural  outcome  of 
the  development  of  the  science,  in  turn,  have  played  a  great  role  in  its 
further  development. 


What  is  Needed  for  the  Advance  of  Therapy 

Since  doctrines  control  therapy,  treatment  will  improve  as  medicine 
advances.  This  involves  the  adaptation  to  medicine  of  all  that  is  ap- 
plicable in  science.  All  progress  in  the  fundamental  branches  eventually 
advances  practice.  The  healing  art  must  give  place  to  the  healing 
science. 

Sound  training  in  the  fundamental  sciences,  in  medicine  and  in  phar- 
macology, constitutes  the  therapeutist's  greatest  asset.  The  doctor  must 
feel  the  responsibility  of  treatment  as  well  as  of  diagnosis.  The  same 
thought  and  individual  efifort  accorded  diagnosis  must  also  be  accorded 
treatment.  Individualistic  diagnosis  must  not  be  followed  by  book  treat- 
ment. Common  sense  individualized,  and  not  book  authority,  is  needed 
in  treatment. 

Pharmacology  is  young.  Science,  like  history,  is  built  by  individuals. 
Individual  effort  in  research  is  the  basis  of  progress  in  pharmacology. 
Dosage  must  be  reduced  to  a  matter  of  certainty.  In  the  absence  of 
chemical  entities,  standardization  of  drugs  and  units  are  greatly  needed, 
otherwise  accuracy  of  dosage  is  impossible.  Treatment  should  always 
be  conducted  after  the  manner  of  a  scientific  investigation.  The  remedy 
and  dosage  once  decided,  throughout  treatment,  careful  observations  must 
be  made  with  adequate  record  of  results.  Daily  notations,  keeping  in 
mind  the  disease  and  the  treatment,  markedly  increase  the  physician's 
capacity  as  a  therapeutist.  Graphic  methods  of  record  such  as  electro- 
cardiograms and  fluid  balance  charts  are  most  desirable. 

Leadership  on  the  part  of  leaders  of  medicine  is  needed.  Therapeutic 
nihilism  or  failure  to  utilize  useful  remedial  measures  on  the  part  of 
teachers  of  medicine  engenders  neglect  of  therapy  in  the  mind  of  the 
student.  Organized  effort  is  necessary  to  combat  the  growing  evils  of 
advertising  on  the  part  of  proprietary  pharmaceutical  interests.  The 
physician  must  see  to  it  that  treatment  rests  on  the  basis  of  science,  and 
not  on  the  claims  of  drug  houses. 

It  is  interesting  to  note  that  progress  in  therapy  has  been  associated 
with  a  marked  decrease  in  the  number  of  drugs  used.  The  application 
of  science  has  revealed  true  values  as  a  result  of  which  the  majority  of 
drugs  have   fallen   into   disuse.     There  is,   however,   great   room    for 


BIBLIOGRAPHY  921 

further  progress  along  such  lines.     New  drugs  are  needed,  but  for  each 
one  adopted  many  should  be  discarded. 

The  complexity  of  the  human  organism,  of  life  processes  and  to  a 
less  extent  of  drugs  demands  breadth  and  depth  in  investigation,  the 
details  of  which  are  usually  beyond  one  individual.  Group  investigation 
is  as  greatly  needed  as  group  practice.  In  chemotherapy,  chemistry  and 
experimental  medicine  are  represented,  but  chemical  detail  is  usually  best 
handled  by  chemists  and  therapeutic  detail  by  physicians.  Each  deserves 
the  best  individual  effort  of  a  specialist.  The  master  mind  must  deal  with 
the  fundamental  conception  and  with  close  scrutiny  of  all  details  rather 
than  with  their  actual  execution.  This  involves  organization  and  great 
expenditure  of  time.  In  America  one  of  the  greatest  needs  of  modern 
medicine  is  a  national  institute  for  pharmacological  research. 

BIBLIOGRAPHY 

(The  articles  listed  include  the  more  general  and  collective  summaries  and 
relatively  few  of  the  more  specific  articles  quoted  in  the  text.) 

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1894. 

GARRISON,  F.  H.:  An  Introduction  to  the  History  of  Medicine.     Phila- 
delphia, 191 7. 

BAASS :  Author  of  the  History  of  Medicine.    New  York,  1910. 

2.  BARKER,    L.    F.,    and    SLADEN,    F.    J.:    Tr.    Ass.    Am.    Phys.,    1912, 

XXVII,  484. 

3.  BRUNTON,   L. :   Goulstonian  Lectures :   Pharmacology  and  Therapeutics. 

London,  1880,  10. 

4.  BERNARD,   €.:    Compt.   rend.    Soc.   de   biol.,    Paris,    1850,    XXX,    1533; 

1856,  XLIII,  825. 

5.  BRODIE,  B.:  Phila.  Trans.,  1812,  205. 

6.  CRUM,  BROWN,  and  ERASER:  Trans.  Roy.  Soc.  Edinb.,  1869,  XXV,  151. 

7.  WOOD,  H.  C.:  A  Treatise  on  Therapeutics,  1876. 

8.  LANGLEY,  J.  N.:  Jour.  Physiol.,  1898,  XXIII,  240. 

9.  MEYER,  H.  H.,  and  GOTTLIEB,  R.:  Pharmacology,  Experimental  and 

Clinical.    Philadelphia,  1914,  139. 

10.  EHRLICH,  P.:  Studies  in  Immunity.    Bolduan,  New  York,  1910,  404. 

11.  BAYLISS,  W.  M.:  General  Principles  of  Physiology.     New  York,  1915. 

12.  ABEL,  J.  J.,  and  ROWNTREE,  L.  G.:  Jour.  Pharm.  and  Exper.  Therap., 

1909,  I,  231. 

13.  ROWNTREE,  L.  G.,  HURWITZ,  S.  H.,  and  BLOOMFIELD,  A.  L.:  Johns 

Hopkins  Hosp.  Bull.,  1913,  XXIV,  327. 

14.  ROWNTREE,  L.  G.,  and  GERAGHTY,  J.  T.:  Arch.  Int.  Med.,  1912,  IX, 

284. 

15.  STAHLSCHMIDT:  Poggendorfif's  Annalen,  1859,  CVIII,  523;  quoted  from 

Crum,  Brown  and  Eraser. 

16.  EHRLICH,  P.:  Loc.  cit. 


922      THE  PHARMACOLOGICAL  BASIS  OF  MEDICINE 

17.  MACHT,   D. :  Jour.   Pharm.   and   Exper.  Therap.,    1915,  VII,   339;    1916, 

VIII,  I   and  451;  1917,  IX,   121,  473,  and  351;   19^7-18,  X,  95;   1918, 
XI,  389  and  419;  1919,  XII,  255. 

18.  HUNT,  R. :  Arch.  Internat.  de  Pharmacodyn.,  1904,  XII,  448. 

19.  BARGER,  G.,  and  DALE,  H.  H.:  Jour.  Physiol.,  1910-11,  XLI,  19  and  51. 

20.  EHRLICH,   P.:  The  Experimental   Chemotherapy  of   Spirilloses,  Ehrlich, 

and  Hata,  translated  by  Newbold.    New  York,  191 1. 

21.  LEVERAN,  C.  L.  A.,  and  MESNIL,  F.:  Trypanosomes  and  Trypanoso- 

miasis.   Paris,  1912. 

22.  THOMAS,  H.  W.:  Brit.  Med.  Jour.,  1905,  I,  1140. 

23.  ROWNTREE,  L.  G.,  and  ABEL,  J.  J.:  Jour.  Pharm.  and  Exper.  Therap., 

1910-11,  II,  loi  and  501. 

24.  HATA,  S.:  The  Experimental  Chemotherapy  of   Spirilloses,  Ehrlich,  and 

Hata,  translated  by  Newbold.     New  York,  191 1. 

25.  METCHNIKOFF:  Ann.  de  ITnst.  Pasteur,  1907,  XXI,  753. 

26.  UHLENHUTH,  P.,  HOFFMAN,  E.,  and  WEIDANZ,  O.:  Deutsch.  Med. 

Woch.,  1907,  XXXIII,  1590. 

27.  LEVADITI,  C,  and  YAMANOUCHI,  T.:  Compt.  rend.  Soc.  de  biol.,  Paris. 

1908,  LXIV,  911. 

28.  LESSER,  E.:  Deutsch.  Med.  Woch.,  1907,  XXIII,  1076,  1313,  1559. 

29.  NEISSER,  E.:  Deutsch.  Med.  Woch.,  1908,  XXXIV,  1500. 

30.  TRUFFI,  M.:  Centralb.  f.  Bakt.,  1908-09,  XLVIII,  Abt.  I,  597,  and  LII, 

Abt.  I,  555. 

31.  CARREL,  A.,  and  DEHELLY,  G.:  Infected  Wounds,  translated  by  Childs. 

New  York,  1917. 

32.  DAKIN,  H.  D.,  COHEN,  J.  B.,  DAUFRESNE,  M.,  and  KENYON,  J.: 

Proc.  Roy.  Soc.    London,  1915-17,  LXXXIX,  232. 

33.  LUSK,  G. :  Science  of  Nutrition.     Philadelphia,  3d  ed.,  1917. 

34.  LIEBIG,  J.:  Die  organische  Chemie  in  ihrer  Anwendung  auf  Physiologic 

u.  Pathologic,  1842. 

35.  PETTENKOFFER:  Annal.    de  Chem.  Pharmakol.,  Supplement  2,  1862. 

36.  DUBOIS,  E.:  Arch.  Int.  Med.,  191 5,  XV,  793-939;  1916,  XVII,  855-1010; 

1917,  XIX,  823-931. 

37.  OSBORNE,  T.  B.,  and  MENDEL,  L.  B.:  Trans.  Fifth  Internat.  Congress 

of  Hygiene  and  Dermograph;  Jour.  Biol.  Chem.,  1912,  XII,  81. 

38.  McCOLLUM:  Jour.  Biol.  Chem.,  1912-13,  XIII,  209. 

39.  ABDERHALDEN,  E. :   Synthese  der  Zellbausteine   in   Pflanze  und  Tier. 

Berlin,  1912. 

40.  FUNK,  C. :  Jour.  Physiol.,  1911-12,  XLIII,  395, 

41.  BARGER,  G. :  The  Simpler  Natural  Bases,  1914,  112. 

42.  HOPKINS,  F.  G.:  Jour.  Physiol.,  1912,  XLIV,  425. 

43.  STARLING,  E.  H.,  and  BAYLISS,  W.  M.:  Lancet,  1905,  II,  339,  423,  501, 

and  579;  Proc.  Roy.  Soc.    London,  1904,  LXXIII,  310. 

44.  EDSALL,  D.  L.,  and  MEANS,  J.  H.:  Arch.  Int.  Med.,  1914,  XIV,  897; 

Trans.  Am.  Phys.,  1914,  XXIX,  69. 

45.  HIGGINS,  H.  L.,  and  MEANS,  J.  H.:  Jour.  Pharm.  and  Exper.  Therap., 

1915,  VII,  I. 

46.  ROBERTSON,  T.  B.:  Jour.  Biol.  Chem.,  1916,  XXIV,  416. 

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48.  CANNON,  W.  B.:  Am.  Jour.  Physiol.,  1914,  XXIII,  356. 


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49.  CRILE,  C.  W. :  The  Origin  and  Nature  of  the  Emotions.     Philadelphia, 

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50.  PARRY,  C.  H.:  Collections  from  the  unpublished  medical  writings  of  the 

late  Caleb  Hillier  Parry.    London,  1825. 

51.  GRAVES:  London  Med.  and  Surg.  Jour.,  1835,  VII,  516. 

52.  BASEDOW:  Wochnschr.  f.  de  gea  Heilk.,  1840,  VI,  XIII,  and  XIV. 

53.  GULL:  Trans.  Clin.  Soc.    London,  1873-74,  IV,  180. 

54.  ORD :  Medico-Chirurgical  Trans.,  London,  1878,  LXI,  57. 

55.  KOCHER,  T.:  Arch.  f.  klin.  Chin,  1883,  XXIX,  254. 

56.  SCHIFF,  M.:  Arch.  f.  exper.  Path.  u.  Pharm.,  1884,  XVIII,  25. 

57.  HORSLEY,  v.:  Brit.  Med.  Jour.,  1890,  I,  287. 

58.  MURRAY,  G.  R.:  Brit.  Med.  Jour.,  1892,  I,  449. 

59.  BAUMANN,  E.:  Muench.  med.  Woch.,  1896,  XLVI,  309. 

60.  KENDALL,  E.  C:  Trans.  Assoc.  Am.  Phys.,  1918,  XXIII,  324. 

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LXXXII,  360. 

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LXVI,  870. 

65.  EGGLESTON,  C:  Arch.  Int.  Med.,  191 5,  XVI,  i. 

66.  WHITE,  S.  M.,  and  MORRIS,  R.  E.:  Arch.  Int.  Med.,  1918,  XXI,  740. 
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68.   WALLACE,  G.  B.,  and  RINGER,  A.  L:  Jour.  Am.  Med.  Assoc,   1909, 
LIII,  1629. 


A  Desk  Index  of  Oxford  Medicine  will  be 
issued  following  publication  of  the  last  volume. 

In  the  meantime,  use  the  Table  of  Contents 
at  the  beginning  of  each  chapter. 


CHAPTER  XXIII 

EDEMA 
By  GEORGE   D.   BARNETT 

Table  of  Contents 

Historical 925 

Physiology  of  Fluid  Distribution 926 

The  Starling  Equilibrium 927 

Possible  Changes  That  Favor  Edema  Production 927 

Salt  Effects 928 

Hormone  Effects 929 

Compensation  for  Varying  Capillary  Pressure 93° 

CUnical  Edemas 92° 

The  Edema  of  Circulatory  Failure 93 1 

Pulmonary  Edema 932 

The  Edemas  of  Nephritis 933 

Nutritional  Edemas 935 

Obstructive  Edemas •  93^ 

Inflammatory,  Toxic  and  Allergic  Edemas 937 

The  CUnical  Investigation  of  Edema 93^ 

Bibliography 93^ 

Historical 

Dropsy  has  been  an  outstanding  problem  since  the  beginnings  of  medicine. 
It  is  mentioned  in  the  Ebers  papyrus  and  on  the  clay  tablets  of  medical  prescrip- 
tions of  ancient  Assyria.  Modern  nutritionists  have  noted  with  satisfaction 
the  report  that  2,300  years  ago  HeracHtus,  disgusted  with  mankind,  retired  to  the 
mountains,  lived  on  vegetables  and  herbs  alone,  acquired  dropsy  and  died.  The 
Hippocratic  writers  have  a  good  deal  to  say  about  it,  classifying  it,  regarding  it 
as  a  hquefaction  of  the  tissues  brought  about  by  some  malady  of  the  spleen  and 
treating  it  by  laxatives  and  by  abdominal  puncture,  when  there  was  much  ascites. 
Others  among  the  ancients  thought  dropsy  due  to  a  disorder  of  the  liver,  as  often 
it  doubtless  was.  Saliceto  in  1275  mentioned  an  association  with  scanty  urine 
and  hardened  kidneys,  but  otherwise  the  medieval  writings  are  not  enlightening. 
Even  Sydenham,  who  gives  so  vivid  a  description  of  cardiac  edema,  does  not 
mention  a  suspicion  that  the  heart  might  be  at  fault.  In  the  XVIII  Century 
Morgagni  found  valvular  defects  in  many  cases  of  dropsy  but  did  not  carry  the 

COPYRIGHT   1947   BY  THE  OXFORD   UNIVERSITY  .PRESS,  NEW  YORK,  INC. 

925 


926  EDEMA 

matter  farther.  Withering  knew  no  distinction  between  cardiac  and  renal  dropsy 
and  was  disappointed  that  cerebral  and  ovarian  dropsies  did  not  yield  to  the  fox- 
glove. Not  until  two  hundred  years  after  Harvey  was  edema  recognized  as  a 
symptom  common  to  many  disease  pictures,  and  this  we  owe  to  Corvisart,  to 
Laennec  and  especially,  to  Bright. 

A  rational  consideration  of  the  mechanism  of  dropsy  also  began  early  in  the 
last  century,  when  the  rise  of  clinical  physiology  brought  numerous  suggestions, 
such  as  the  lymphatic  obstruction  hypothesis  of  Broussais,  the  increased  capillary 
filtration  of  the  Ludwig  school  and  Heidenhain's  idea  of  augmented  lymph  secre- 
tion. Present  concepts  date  from  1896  when  Starling^^  first  pointed  out  clearly 
that  a  balance  between  hydrostatic  and  osmotic  forces  determines  fluid  move- 
ment through  the  capillary  walls  and  is,  consequently,  concerned  primarily  in 
edema  formation.  For  fifty  years  the  hypothesis  has  served  those  who  have 
wished  to  understand  edemas.  There  have  been  some  clinical  discrepancies,  and 
the  recent  studies  of  electrolyte  and  water  balance^"'"  have  made  it  plain  at 
least  that  we  have  not  arrived  yet  at  a  complete  knowledge  of  the  physiology  of 
edema.  A  brief  consideration  of  some  of  the  factors  that  influence  fluid  distribu- 
tion in  the  body  will  permit  an  understanding  of  some  of  the  mechanisms  con- 
cerned. 

The  Physiology  of  Fluid  Distribution 

Edema  is  a  local  or  general  increase  in  the  interstitial  fluid  of  the  body. 
Normally  the  interstitial  compartment  is  separated  from  the  blood  plasma  by 
the  capillary  endothelium,  a  membrane  through  which  water  and  crystalloid  sub- 
stances pass  with  ease,  but  which  is  largely  impermeable  to  colloids,  chiefly  the 
proteins  of  the  plasma.  It  is  separated  from  the  intracellular  fluid  by  the  cell 
walls,  which  are  permeable  to  water  but  not  freely  so  to  electrolytes,  to  proteins 
or  to  most  other  solutes.  Membrane  permeabilities  within  the  body  probably 
are  never  absolute;  normal  interstitial  fluid  probably  contains  a  small  amount 
of  protein^^,  and  the  conditions  under  which  variations  in  permeability  may 
occur  frequently  are  not  understood.  The  interstitial  fluid  constitutes  the  im- 
mediate internal  environment  of  the  body  cells,  and  its  volume  and  the  total  os- 
molar  content  of  its  dissolved  substances  are  maintained  at  quite  constant  levels 
by  gain  or  loss  of  fluid  from  or  to  the  vascular  or  cellular  compartments  and  in- 
directly, by  excretion  or  retention  of  water  or  solutes  by  the  kidneys'"'  '^. 

Fluid  transfer  through  the  capillary  walls  is  of  especial  importance  in  the 
edema  problem.  Normall}^  the  eflfective  hydrostatic  pressure,  which  maintains 
a  constant  flow  from  capillaries  to  tissue  spaces,  is  the  capillary  pressure  minus  the 
tissue  pressure,  and  the  effective  osmotic  pressure,  which  moves  fluid  in  the  op- 
posite direction,  is  the  osmotic  pressure  of  the  plasma  colloids,  chiefly  proteins, 
Vol.  I.  1 147 


THE  PHYSIOLOGY  OF  FLUID  DISTRIBUTION  927 

minus  the  osmotic  pressure  of  the  proteins  in  the  tissue  fluids.*    For  further  dis- 
cussion and  diagrams  see  Vol.  Ill,  Chapter  X  of  Oxford  Medicine. 

The  Starling  Equilibrium 

It  was  this  balance  of  hydrostatic  against  osmotic  forces  that  Starling  postu- 
lated in  1896,  and  its  validity  as  the  immediate  mechanism  by  which  fluids  are 
moved  through  membranes  in  the  body  is  beyond  question.  Landis^^  has  shown 
that  the  actual  measured  pressures  conform  to  the  hypothesis;  Schade'^^  has 
demonstrated  the  mechanism  in  a  laboratory  model,  and  Peters"  reminds  us 
that  the  fact,  that  extracellular  fluid  has  been  shown  to  have  the  composition 
of  an  ultrafiltrate  of  plasma,  is  even  more  substantial  proof  of  its  validity.  Ap- 
parent discrepancies  are  recorded  occasionally  in  the  literature,  but  no  data  are 
given  which  include  measurements  of  the  effective  hydrostatic  and  osmotic 
pressures. 

Possible  Changes  That  Favor  Edema  Production 

There  are  many  possible  changes  in  the  Starling  equilibrium  in  the  direction 
of  edema  production.  If  the  flow  of  lymph  from  a  region  be  obstructed,  the  in- 
creasing tissue  pressure  will  decrease  the  outward  flow  from  the  capillaries  until 
it  equals  the  return  flow  inward,  and  during  this  period  edema  fluid  will  accu- 
mulate. Decrease  in  the  effective  colloid  osmotic  pressure  may  result  from 
diminished  plasma  protein  concentration  or  from  increased  protein  in  the  tissue 
fluids,  due  almost  always  to  increased  permeability  of  the  capillary  endothelium. 
Hypoproteinemia  has  many  possible  causes,  which  Rytand-^  has  outlined 
(Table  I). 

TABLE  I 

Physiological  Causes  of  Hypoproteinemia 
A.  Loss  and  destruction  of  body  protein 
I.  Urine  (Bright's  disease) 
II.  Ascitic  fluid  (cirrhosis  with  paracenteses) 

III.  Tissue  (cachexia) 

IV.  Fetus  (pregnancy) 

*  The  effects  of  hydrostatic  pressure  are  obvious.  The  nature  of  the  osmotic  action  is 
perhaps  clarified  by  noting  that  the  protein  molecules  within  the  capillary,  by  their  mere  presence 
and  because  they  cannot  escape,  obstruct  the  outward  diffusion  of  water  and  dissolved  crystal- 
loids, but  in  the  fluid  of  the  tissue  spaces  there  is  nothing  to  obstruct  their  diffusion  inward. 
The  net  flow  due  to  the  plasma  proteins  is,  therefore,  inward.  By  this  concept  the  osmotic 
force,  which  moves  fluid,  is  derived  from  the  universal  kinetic  energy  of  molecular  movement  and 
need  not  be  regarded  as  a  mysterious  "attractive"  or  "drawing"  force  exerted  upon  water 
molecules  by  dissolved  substances.  By  another  similar  concept  the  net  diffusion  of  water  and 
crystalloid  molecules  is  inward,  because  they  are  in  higher  concentration  outside  than  inside  the 
capillary. 

Vol.  I.  1147 


928  EDEMA 

B.  Retarded  formation  of  serum  protein 
I.  Lack  of  dietary  protein 

(a)  Absolute  total  dietary  insufficiency 
(i)   Starvation 

(2)  Pyloric  obstruction 

(3)  Diarrhea 

(b)  Relative  total  dietary  insufficiency 
(i)   Pregnancy 

(2)  Hyperthyroidism 

(3)  Diabetes  mellitus 

(c)  Dietary  protein  deficiency 
(i)  Low  protein  diet 

(2)  Pancreatic  disease 

n.  Altered  states  of  the  body 

(a)  Normal 

(i)  The  newborn 

(b)  Abnormal 

(i)  Hepatic  disease 

(2)  Bright's  disease 

(3)  Beriberi 

m.  Unexplained 

Increased  capillary  permeability  may  result  from  the  damaging  effect  of  a 
local  or  general  toxic  agent,  and  capillary  dilatation  from  any  cause  probably 
produces  some  degree  of  protein  leak.  So  a  rise  in  tissue  temperature  from  the 
application  of  heat,  from  fever  or  even  from  hot  weather  may  increase  tissue 
fluids.  Nervous  impulses,  normal  or  abnormal,  also  may  increase  capillary  per- 
meability both  by  simple  vasodilatation  and  probably  also  by  a  neurochemical 
mechanism. 

Increase  in  the  effective  capillary  hydrostatic  pressure  may  occur  if  there  is 
obstruction  ahead  in  the  veins,  or  because  of  increased  capillary  volume  if  there 
is  arteriolar  dilatation  or  increased  total  plasma  volume.  Less  obvious  are  the 
effects  of  electrolytes,  especially  sodium  salts,  which  may  have  a  profound  effect 
on  water  distribution  in  the  body^°. 

Salt  Effects 

Physiological  variations  in  the  volumes  of  the  three  fluid  compartments  (vas- 
cular, interstitial,  intracellular)  are  not  normally  very  great.  Fluid  usually  enters 
the  blood  stream  from  the  gastrointestinal  tract.  Selective  absorption  of  water 
and  salts  in  the  intestinal  villi  and  prompt  renal  excretion  of  excesses  of  one  or 
the  other  combine  to  make  the  electrolyte  concentration  changes  in  the  plasma 
minimal.  Whatever  added  volume  of  fluid  remains  in  the  plasma  increases  the 
Vol.  I.  1 147 


THE  PHYSIOLOGY  OF  FLUID  DISTRIBUTION  929 

hydrostatic  pressure  and  decreases  the  colloid  osmotic  pressure  in  some  degree, 
and  both  of  these  changes  lead  to  increased  outflow  from  capillaries  to  interstitial 
fluid.  Thus  salt  solution  retained  for  even  a  short  time  is  distributed  rapidly 
throughout  the  extracellular  compartment.  Large  amounts  will  increase  any 
edema  already  present,  or  the  process  may  combine  with  pathological  factors  to 
produce  an  initial  clinical  edema.  Sufliciently  vigorous  and  prolonged  administra- 
tion of  salt  and  water  may  even  cause  slight  edema  in  normal  subjects.  If  ex- 
perimentally or  as  a  result  of  pathological  conditions  the  interstitial  fluid  becomes 
hypertonic,  there  will  be  an  osmotic  flow  of  water  into  it  from  the  intracellular 
fluid,  and  conversely,  if  interstitial  fluid  becomes  hypotonic,  its  volume  will 
shrink  by  osmotic  transfer  of  water  into  the  cells.  The  occurrence  of  such  a  loss 
of  edema  without  change  in  weight  of  the  patient  has  been  described. 

It  should  be  noted  here  especially  that  the  transfer  of  salt  solution  from 
plasma  to  tissue  spaces  is  to  be  regarded  as  a  simple  consequence  of  the  shift 
in  the  Starling  equilibrium  acting  throughout  the  vast  capillary  membrane,  and 
that  it  implies  no  peculiar  ability  of  the  tissues  to  attract  or  to  retain  salt.  Flow 
of  fluid  in  the  opposite  direction  also  occurs  with  equal  ease  whenever  the  balance 
shifts  to  require  it.  This  usually  involves  renal  excretion  of  salt  and  water  with 
reduction  in  plasma  volume  and  capillary  hydrostatic  pressure  and  increase  in 
plasma  colloid  osmotic  pressure.  The  kidney  can  excrete  excess  salt  or  excess 
water  as  the  occasion  demands,  and  slight  hypotonicity  or  hypertonicity  probably 
can  be  an  adequate  stimulus,  but  beyond  this  the  conditions  under  which  body 
fluid  volumes  are  regulated  and  how  they  are  regulated  by  the  kidneys  is  not 
understood  completely.  Some  of  the  factors  involved  are  the  volume  of  blood 
flow  to  the  kidneys,  the  number  of  active  glomeruli  and  the  acceptance  or  rejection 
of  water  or  electrolytes  by  the  tubule  cells2^^^\  It  is  here  that  certain  of  the 
hormones  are  active. 

Hormone  Effects 

An  antidiuretic  substance  is  elaborated  by  the  pituicytes  of  the  neurohypoph- 
ysis and  may  be  identical  with  the  pressor  hormone  pitressin.  It  controls 
effectively  the  polyuria  of  diabetes  insipidus  and  participates  in  the  normal 
fluid  balance.  The  steroid  hormones  of  the  adrenals  and  gonads  are  concerned 
also  with  electrolyte  and  water  balance^^  and  thus  indirectly  with  the  edema  prob- 
lem. In  Addison's  disease  deficiency  of  the  adrenal  cortical  hormone  leads  to  a 
low  level  of  the  sodium  salts  in  the  plasma,  to  dehydration,  to  low  plasma  volume 
and  to  shock.  Replacement  therapy  with  cortical  extract  or  desoxycorticosterone 
may  then  so  increase  the  salt  and  water  content  of  the  extracellular  fluid  that 
general  edema  results.  The  action  of  the  adrenal  cortical  hormone  is  upon  the 
renal  tubules,  promoting  reabsorption  of  sodium  salts.    Most  of  the  hormones 

Vol.  I.  1 147 


930 


EDEMA 


of  the  ovary  and  testis  are  said  to  promote  retention  of  water  and  sodium  salts'^, 
but  their  mode  of  action  has  not  been  estabhshed.  Lack  of  thyroid  hormone 
brings  about  in  some  manner  an  increase  in  soluble  colloid  material,  probably 
mucoprotein,  in  the  interstitial  fluid.  The  effective  colloid  osmotic  pressure  of 
the  plasma  is  reduced  and  edema  results.  Fluid  retention  is  seen  also  at  times 
during  insulin  therapy,  rarely  with  slight  but  definite  edema,  especially  in  patients 
recovering  from  coma.  Excessive  infusions  of  salt  solution  as  well  as  some 
lowering  of  the  plasma  proteins  from  a  dietary  cause  not  related  to  insulin  are 
responsible  frequently.    A  true  hormonal  action  here  is  doubtful. 

Compensation  for  Varying  Capillary  Pressure 

Hydrostatic  pressure  in  the  capillaries  varies  widely  in  different  parts  of  the 
body.  In  the  standing  position  gravity  increases  the  pressure  greatly  in  the  legs, 
and  pressures  are  believed  to  be  low  in  the  capillaries  of  the  lungs  and  of  the 
liver.  Since  the  colloid  osmotic  pressure  of  the  plasma  is  presumably  about  the 
same  throughout  the  circulation,  the  question  must  arise  as  to  how  a  balance 
can  be  obtained.  Partial  answers  are  available.  In  the  liver  a  high  protein 
content  of  the  tissue  fluid  lowers  the  effective  colloid  osmotic  pressure  and  is 
evidenced  by  high  protein  figures  in  liver  lymph^^.  It  has  been  suggested  that 
this  is  protein  newly  formed  in  the  liver.  In  the  lower  extremities  lymph  flow  is 
greater,  indicating  that  outflow  from  the  capillaries  is  maintained  there  at  a 
higher  level.  Local  increase  in  capillary  permeability  is  another  possible  adjust- 
ment to  offset  low  capillary  hydrostatic  pressure,  but  good  evidence  of  such  a 
compensation  is  lacking.  It  is  of  some  teleological  interest  to  note  that  in  the 
lungs  the  low  capillary  pressure  is  strikingly  adapted  to  the  maintenance  of  dry- 
ness in  the  alveoli. 

Imbibition  of  water  by  the  colloids  of  the  tissue  cells  under  the  influence  of 
environmental  changes  has  been  considered  important  in  edema  formation,  but 
edema  fluid  is  essentially  interstitial,  and  the  chief  known  changes  that  take 
place  in  intracellular  fluid  volume  are  osmotic,  the  result  of  differences  in  con- 
centrations of  electrolytes  inside  and  outside  the  cells.  The  contribution  of  col- 
loid imbibition  to  edema  is  small,  and  the  occasions  of  its  participation  are  not 
known. 

Clinical  Edemas 

Edema  is  nearly  always  a  pathological  finding,  although  occasionally  small 
local  accumulations  of  excess  tissue  fluid  may  be  recognizable  in  normal  in- 
dividuals. A  transient,  slight  swelling  of  the  eyelids  and  periorbital  tissues  may 
be  present  in  some  persons  on  arising  in  the  morning,  and  others  may  show  a  slight 
edema  of  the  ankles  on  prolonged  quiet  standing. 

Vol.  I.  1 147 


CLINICAL  EDEMAS  931 

The  interstitial  space  is  very  distensible,  and  weight  curves  in  certain  patients 
show  that  it  can  accept  as  much  as  eight  or  ten  liters  before  edema  appears. 
Bedside  recognition  of  minimal  edema  is  occasionally  uncertain,  and  opinions 
may  differ  in  a  given  case.  The  phenomenon  of  pitting,  by  which  we  commonly 
demonstrate  subcutaneous  edema,  is  merely  the  displacement  of  freely  movable 
fluid  in  the  intercommunicating  tissue  spaces,  but  sufficient  pressure  maintained 
suflSciently  long  will  produce  pitting  in  the  normal  subject,  and  the  borderUne 
between  normal  and  pathological  pitting  thus  is  not  sharp.  Edema  that  has 
been  present  a  long  time  is  apt  to  become  hard  and  to  pit  with  difficulty.  This 
is  said  to  be  due  to  connective  tissue  proliferation.  In  myxedema  there  is  said 
to  be  a  nonpitting  edema,  but  if  the  fluid  resides  in  the  intercellular  spaces  and 
not  in  the  tissue  cells,  the  term  is  without  meaning.  True  non-pitting  edema, 
other  than  the  weight  increase  usually  called  pre-edema,  probably  is  non-existent. 

The  Edema  of  Circulatory  Failure 

Cardiac  edema  usually  is  a  late  manifestation  of  heart  failure.  Frequently 
it  is  noticed  first  as  a  slight  swelling  above  the  shoetops,  present  in  the  evening 
and  gone  the  next  morning,  and  examination  at  this  time  will  show  distention 
of  the  neck  veins,  which  also  disappears  promptly  with  rest.  Often  preceding 
this  edema  there  has  been  a  long  period  of  increased  load  upon  the  left  ventricle, 
such  as  hypertension,  aortic  valve  disease,  with  gradual  asymptomatic  hypertro- 
phy and  dilatation,  later  dyspnea,  and  with  physical  findings  due  to  pulmonary 
congestion  or  frank  pulmonary  edema.  This  common  clinical  sequence  from  the  left 
ventricle  through  the  lungs  to  the  systemic  veins  strongly  supports  the  backward- 
failure  hypothesis  of  cardiac  insufficiency  with  its  corollary  that  the  edema  of 
heart  failure  is  due  immediately  to  the  increased  intracapillary  pressure  which 
must  follow  venous  congestion.  Starling  proposed  this  mechanism^-,  and  many 
investivations  have  served  to  confirm  it.  Landis  and  others  ^^  have  shown  that 
even  a  small  rise  in  venous  pressure  is  sufficient  to  cause  measurable  amounts  of 
fluid  to  accumulate  in  the  tissues  and  recently  Landis  and  associates-^  have  re- 
ported that,  after  experimental  cardiac  damage  of  several  kinds  in  dogs,  exercise 
produces  elevation  of  venous  pressure,  whereas  in  normal  dogs  it  is  reduced  by 
similar  exercise.  It  seems  proven,  therefore,  that  a  chief  immediate  cause  of  the 
edema  of  congestive  heart  failure  is  increased  hydrostatic  pressure  in  the  capil- 
laries, and  that  the  effective  increase  is  at  first  that  which  occurs  during  exercise. 
Some  decrease  in  plasma  proteins  is  not  an  uncommon  finding  in  heart  failure 
and  is  the  sum  of  several  items^^.  The  diet  is  often  low  in  protein,  and  with  severe 
congestion  loss  in  the  urine  may  be  considerable.  Late  in  heart  failure  there  is 
usually  a  significant  increase  in  blood  volume-^  in  which  both  hydremia  and  in- 
creased permeability  due  to  anoxia  may  contribute  to  the  lowered  plasma  pro- 
VoL.  I.  1 147 


932  EDEMA 

tein  percentage,  and  finally  the  congested  liver  may  be  unable  to  produce  new 
protein  at  an  adequate  rate.  Although  the  plasma  protein  levels  are  never  very- 
low,  any  decrease  will  contribute  to  the  acciunulation  of  edema  fluid. 

Increased  permeability  of  the  capillary  walls  as  a  result  of  anoxia  is  mentioned 
often  as  a  factor  in  cardiac  edema.  Landis  has  demonstrated  that  lack  of  oxygen 
will  make  the  endothelium  more  permeable,  but  the  degree  of  anoxia  in  his  ex- 
periments is  greater  than  that  usually  found  in  any  but  terminal  stages  of  heart 
failure.  A  necessary  result  of  increased  permeability  would  be  a  high  concentra- 
tion of  protein  in  the  edema  fluid.  Reported  values  vary  considerably  but  do  not 
indicate  any  significant  leakage  of  protein.  The  protein  concentrations  found  in 
cardiac  edema  fluids  also  do  not  show  any  correlation  with  the  duration  of  the 
edema.  So  it  must  be  concluded  that  the  integrity  of  the  capillary  wall  ic  rarely 
much  impaired. 

Increase  in  the  sodium  salt  content  of  the  body  will  bring  about  an  increase 
in  extracellular  fluid  volimie  in  cardiac  patients  as  well  as  in  normals  and  thus 
will  promote  edema  formation.  With  failure  of  the  circulation  there  may  be  a 
marked  reduction  in  blood  flow  to  the  kidneys*^  with  impaired  excretion  of  sodium 
salts  and  water.  This  would  increase  an  edema  already  present,  but  that  such  a 
mechanism  is  ever  active  early  in  the  course  of  heart  failure  is  unlikely. 

Hydrothorax  of  some  degree  is  almost  a  constant  part  of  the  edema  of  late 
heart  failure.  Its  appearance  earlier  and  more  extensively  on  the  right  side  is 
an  old  clinical  observation  which  has  had  several  explanations  such  as  the  pres- 
sure of  the  enlarging  heart  on  the  right  pulmonary  vein  or  stasis  in  the  azygos 
vein.  Dock  believes  that  like  other  cardiac  edema  it  is  localized  by  gravity,  as 
there  is  a  longer  return  course  of  blood  from  the  right  lung  than  from  the  left. 
Right  lateral  decubitus  thus  will  favor  its  accumulation. 

Pulmonary  Edema 

Intracapillary  pressure  is  considerably  lower  in  the  lung  than  in  the  systemic 
circulation,  and  the  Starling  balance  thus  should  be  displaced  in  favor  of  dryness 
in  the  alveoli.  The  ability  of  the  pulmonary  capillaries  to  absorb  fluid  from  the 
air  cells  is  in  fact  extraordinary.  Drinker^^  cites  the  experiment  of  Colin,  who 
in  1873  poured  21  liters  of  water  into  the  trachea  of  a  horse  in  a  period  of  3^  hours 
without  ill  effect. 

Acute  pulmonary  edema ^-'  ^^  occurs  commonly  in  patients  with  heart  failure. 
Its  association  with  long-standing  overwork  of  the  left  ventricle  is  so  striking 
that  the  conclusion  seems  justified  that  left  ventricular  failure  with  increased 
pressure  throughout  the  pulmonary  circulation  is  an  important  mechanism  in  its 
production.  Welch^^  suggested  such  an  explanation  in  1878  and  supported  it 
with  animal  experimentation,  but  Wiggers^^  was  unable  to  produce  pulmonary 
Vol.  I.  II4P 


CLINICAL  EDEMAS  933 

edema  in  dogs,  in  which  very  high  capillary  pressures  were  maintained  for  thirty 
minutes,  and  believes  that  back-pressure  alone  rarely  can  account  for  acute  pul- 
monary edema  in  man.  The  frequent  occurrence  of  attacks  of  acute  pulmonary 
edema  during  the  night,  when  left  ventricular  recuperation  should  be  greatest, 
has  been  an  enigma.  Acute  myocardial  strain  from  disturbing  dreams  has  been 
suggested,  but  a  more  likely  cause  is  a  nocturnal  increase  in  blood  volume  in 
the  lung  as  a  result  of  rest^'-.  Systemic  venous  congestion  is  relieved  and  re- 
absorption  of  tissue  fluid  may  occur.  The  bout  of  dyspnea,  which  often  begins 
the  attack,  also  may  favor  transudation  by  lowering  intrathoracic  pressure. 

Other  factors  may  be  active  also  in  the  production  of  acute  pulmonary  edema. 
Drinker  believes  that  increase  in  capillary  permeability  may  have  even  greater 
influence  than  pressure  changes.  The  lung  capillaries  are  particularly  sensitive 
to  oxygen  lack,  and  since  their  endothelial  cells  receive  their  oxygen  from  the  air, 
any  interference  with  the  air  supply  may  initiate  local  or  general  puhnonary 
edema.  Alveolar  transudation  then  further  decreases  the  oxygen  supply,  and  a 
vicious    cycle    becomes  active,   endothelial  anoxia  —  transudation  —  increased 

anoxia. 

Nervous  influences  are  active  also.  The  nervous  mechanism  may  be  excited 
directly  as  in  the  pulmonary  edema  which  occasionally  accompanies  skull  frac- 
ture or  encephaUtis,  or  reflexly  as  in  the  "albmninous  expectoration"  of  para- 
centesis. The  frequent  brilliant  therapeutic  effect  of  morphine  in  acute  pulmonary 
edema  is  to  be  ascribed  to  the  sedation  of  nervous  impulses.  The  mode  of  action 
of  neurogenic  influences  is  unknown,  but  a  local  pulmonary  neurochemical  mech- 
anism has  been  suggested. 

The  edema  produced  by  inflammation  or  by  irritant  gases  presumably  is 
identical  with  the  edema  of  inflammation  elsewhere. 

It  is  evident  that  a  variety  of  elements  may  contribute  to  produce  alveolar 
transudation  in  the  lungs  and  that  clinically  the  situation  may  be  complex  and 
not  subject  to  exact  analysis. 

The  Edemas  of  Nephritis 

The  edema  of  acute  nephritis  usually  is  slight  and  may  escape  notice  alto- 
gether. A  little  puffiness  about  the  eyes  and  of  the  face  is  common,  and  there 
may  be  a  small  amount  of  subcutaneous  edema  elsewhere.  Widespread  edema 
has  been  reported  rarely,  but  many  such  cases  may  include  edema  from  an  early 
nephrotic  stage  or  from  the  heart  failure  which  is  seen  occasionally  in  acute  neph- 
ritis.   Exact  determination  of  the  cause  of  the  edema  is  sometimes  difficult. 

The  nature  of  the  edema  of  acute  nephritis  is  in  some  doubt.  That  there  is 
widespread  vascular  damage  is  plain  from  the  occurrence  of  hematuria  and  of 
retinal  hemorrhages,  and  it  is  evident  that  the  capillary  wall  must  have  lost  in 
Vol.  I.  1 147 


934  EDEMA 

some  degree  its  efficiency  as  a  membrane  semipermeable  to  the  plasma  colloids. 
Edema  fluid  resulting  from  such  a  breakdown  would  have  of  necessity  a  high 
protein  content,  and  here  the  reported  figures  are  not  in  agreement.  However 
it  will  be  noted  that  the  figures  of  Warren  and  Stead^^  for  acute  nephritis  are 
higher  than  they  found  in  the  edema  fluid  of  heart  failure  and  considerably  higher 
than  those  reported  for  the  edema  of  nephrosis.  Capillary  damage  is,  therefore, 
probably  a  principal  part  of  the  mechanism. 

The  most  striking  edema  of  renal  disease  is  the  widespread  and  persistent 
edema  characteristic  of  the  active  (subacute)  or  nephrotic  stage  of  glomerulo- 
nephritis and  in  the  other  nephroses  with  high  albuminuria.  It  is  of  interest 
that  Bostock'*,  a  chemist  who  worked  on  Bright's  edematous  patients,  reported: 
"I  think  I  may  venture  to  say  that  the  serum  generally  in  these  cases  contained 
less  albumin  than  in  health,  although  I  am  not  able  to  state  precisely  the  amount 
of  the  difference".  CHnicians  long  believed  that  loss  of  protein  in  the  urine  led 
to  a  watery  condition  of  the  blood  which  favored  transudation,  and  not  until 
Epstein's  valuable  contribution  in  191 7  were  the  Starling  concepts  used  to  ex- 
plain this  edema.  Epstein^^  pointed  out  that  the  plasma  proteins,  depleted  by 
excessive  loss  of  protein  through  the  kidneys,  were  no  longer  able  to  bring  about 
the  normal  return  of  fluid  from  the  tissue  spaces  to  the  blood.  Clinical  observa- 
tions have  confirmed  abundantly  the  correctness  of  this  interpretation,  and  the 
plasmapheresis  experiments  of  Leiter  and  of  Barker  and  Kirk  have  been  further 
elucidating.  They  show  that  by  lowering  the  plasma  protein  in  dogs  a  level  is 
reached  at  which  edema  occurs  with  great  regularity,  and  the  animal  recovers 
completely,  when  the  plasma  protein  level  is  restored  to  the  normal  range.  The 
edema  of  nephrosis  differs  somewhat  from  this  experimental  edema,  because  the 
protein  lost  in  the  urine  is  principally  albumin  instead  of  the  mixed  albumin  and 
globulin  of  plasma.  The  globulin  fraction  of  the  remaining  plasma  proteins  is, 
therefore,  greater  than  normal.  Globulin  molecules  are  large  and  exert  less 
osmotic  pressure,  gram  for  gram,  than  do  molecules  of  albumin;  so  the  level  of 
total  plasma  protein,  at  which  edema  may  occur,  is  a  variable  one  and  will  de- 
pend on  the  albumin-globulin  ratio.  There  is  also  at  times  a  lack  of  correlation 
between  the  amount  of  protein  losses  and  the  plasma  protein  level.  In  some 
patients  the  plasma  protein  concentration  may  be  low  after  relatively  small 
losses  in  the  urine,  while  in  others  large  losses  may  cause  only  slight  lowering  of 
plasma  levels.  Variations  in  the  ability  to  replenish  plasma  proteins  seems 
probable. 

Spontaneous  disappearance  of  the  edema  may  take  place,  while  the  plasma 
proteins  are  still  low,  and  such  findings  are  cited  to  discredit  the  StarUng  hypothe- 
sis. These  discordant  data,  however,  never  include  measurements  of  effective 
osmotic  or  hydrostatic  pressures.  Furthermore  it  should  be  remembered  that 
in  the  nephrotic  edemas  the  Starling  equilibrium  may  be  operative  at  a  low  level. 

Vol.  I.  1 147 


CLINICAL  EDEMAS  935 

Low  colloid  osmotic  pressure  because  of  low  plasma  protein  is  balanced  by  low 
hydrostatic  pressure  because  of  increased  tissue  pressure.  Loss  of  edema  may 
well  begin  in  response  to  slight  lowering  of  the  hydrostatic  pressure  at  very  low 
levels  of  plasma  protein.  Even  slight  diuresis,  the  mechanisms  for  which  are 
not  clearly  understood,  might  be  an  initiating  factor.  Warren,  Merrill  and 
Stead^^  point  out  that  the  increased  tissue  pressure  due  to  edema  is  an  important 
factor  in  determining  the  size  of  the  plasma  volume  in  patients  with  low  plasma 
protein  levels.  The  decrease  in  colloid  osmotic  pressure  of  the  plasma  is  com- 
pensated for  by  the  increase  in  tissue  pressure,  usually  permitting  the  patient 
to  maintain  an  adequate  blood  volume. 

Finally  in  nephritis  we  may  have  the  edema  of  heart  failure,  including  acute 
pulmonary  edema,  as  a  part  of  the  clinical  picture.  This  is  seen  most  often 
late  in  the  disease,  when  heart  failure  results  from  the  long-standing  hyperten- 
sion. When  heart  failure  supervenes  during  or  closely  following  the  active  stage 
of  a  glomerulonephritis,  clinical  distinction  between  renal  and  cardiac  responsi- 
bility for  the  edema  may  be  impossible. 

In  the  treatment  of  nephrotic  edema  restriction  of  salt  may  be  of  value,  but 
the  results  are  often  unsatisfactory  and  erratic^.  Attempts  to  raise  the  plasma 
protein  level  by  a  high  protein  diet  are  also  disappointing,  and  by  increasing  the 
work  of  the  kidney  may  be  harmful.  On  the  other  hand  diets  too  low  in  protein 
may  add  more  edema  to  the  picture.  The  use  of  human  plasma  albumin^ 
intravenously  may  be  effective  when  available,  but  large  amounts  are  necessary, 
retention  of  about  75  grams  of  albumin  being  required  to  bring  about  an  increase 
of  one  per  cent,  in  the  plasma  protein  level,  and  with  continuing  albuminuria  a 
lasting  effect  cannot  be  expected.  The  substitution  of  other  colloids  has  been 
practiced  extensively,  such  as  acacia  or  pectin.  While  they  are  effective  in  re- 
ducing the  edema,  they  are  known  to  diminish  protein  formation  in  the  experi- 
mental animal,  and  their  ultimate  fate  in  the  body  may  entail  other  disadvantages-. 
Their  hazards  appear  to  outweigh  their  usefulness.  With  a  low  salt  diet  water 
need  not  be  restricted  and  may  have  some  diuretic  action.  Other  diuretics  such 
as  the  purines  and  the  organic  mercurials  are  used  often,  but  opinion  is  divided 
as  to  their  harmfulness  in  the  presence  of  kidney  disease.  For  the  relief  of  stub- 
born extreme  edema  South ey  tubes  may  be  used,  and  serous  transudates,  when 
large,  likewise  are  best  removed  by  paracentesis. 

Nutritional  Edema 

In  many  states  of  malnutrition  considerable  edema  may  be  seen.  Lack  of 
vitamins  in  the  diet,  a  low  protein  ration,  failure  to  absorb  or  to  utiUze  vitamins 
and  proteins  because  of  bowel  disease  are  common  etiological  pictures.  Liver 
function  often  is  below  normal  with  impaired  protein  formation  and  low  plasma 

Vol.  I.  1 147 


936  EDEMA 

protein  levels.  In  the  United  States  during  the  depression  years  many  cases  of 
beriberi  with  edema  were  seen,  identifiable  chiefly  by  the  history  of  inadequate 
diets,  the  presence  of  peripheral  neuritis  and  of  greatly  dilated  hearts  which  re- 
turned to  normal  size  promptly  under  vitamin  Bi  therapy.  The  edema  in  these 
patients  is  largely  that  of  heart  failure,  but  some  reduction  of  plasma  albumin 
is  common,  and  in  some  instances  vasomotor  paresis  may  augment  intracapillary 
pressure.  The  starvation  edemas  seen  so  abundantly  in  prison  and  concentra- 
tion camps  form  a  striking  and  appalling  group.  Lack  of  adequate  protein  intake 
and  eventually  the  utilization  of  amino  acids  for  body  fuel  instead  of  protein 
synthesis  combine  to  produce  low  plasma  levels  of  protein.  An  accompanying 
anemia  may  contribute  to  the  edema  by  increasing  capillary  permeability. 

Whether  the  edema  and  ascites  of  Laennec's  cirrhosis  belong  in  the  nutritional 
group  is  not  fully  settled.  The  toxic  agent  responsible  for  the  hepatitis  is  un- 
known, but  a  dietary  factor  is  suspected.  Portal  obstruction  alone  does  not 
produce  ascites  in  experimental  animals  and  probably  not  in  man.  A  low  plasma 
protein  level  is  a  constant  finding  in  the  stage  of  ascites  and  is  the  result  of  im- 
paired protein  formation  in  the  damaged  liver  and  later  the  result  of  the  loss  of 
protein  into  the  ascitic  fluid.  Usually  the  albumin-globulin  ratio  is  diminished 
or  reversed,  and  while  edema  levels  are  not  reached,  the  loss  of  plasma  colloid 
osmotic  pressure  plus  the  increased  capillary  pressure  from  portal  obstruction  will 
account  adequately  for  the  ascites  as  well  as  the  leg  edema.  Partial  obstruction 
of  the  vena  cava  by  the  ascites  is  often  mentioned  as  a  factor,  but  evidence  of 
obstruction  of  the  venous  return  from  the  legs  usually  is  lacking.  Treatment  of 
the  edema  and  ascites  of  portal  cirrhosis  with  diuretics  is  unsatisfactory,  and 
treatment  directed  toward  the  relief  of  the  underlying  liver  disease  also  is  dis- 
couraging in  cases  which  have  progressed  to  this  stage. 

Obstructive  Edema 

Edema  resulting  from  obstruction  to  veins  or  lymphatics  is  common.  Uni- 
lateral or  unequal  edemas  of  the  legs  are  most  frequently  the  result  of  venous 
obstruction  from  thrombosis  or  varicosities.  Edema  from  the  pressure  of  an 
enlarging  uterus  or  a  malignant  tumor  also  is  not  infrequent.  Whether  or  not 
occlusion  of  a  vein  will  cause  edema  depends  upon  the  amount  of  collateral  cir- 
culation available  and  upon  the  presence  or  absence  of  other  factors  which  might 
contribute  to  edema  formation.  In  experimental  animals  edema  seldom  occurs 
after  ligation  of  even  large  veins  such  as  the  femoral  or  the  inferior  vena  cava, 
and  in  man  such  edema  may  be  transient,  disappearing  with  the  development  of 
collateral  channels.  In  cachectic  individuals  even  moderate  degrees  of  venous 
obstruction,  such  as  may  result  from  an  unusual  position  in  bed,  may  result  in 
edema.    Here  low  plasma  proteins  are  a  frequent  contributing  factor.  In  patients 

Vol.  I.  1 147 


CLINICAL  EDEMAS  937 

with  congestive  heart  failure  venous  thrombosis  may  occur  as  a  result  of  stasis, 
and  local  edema  due  to  minor  thromboses  is  seen  not  infrequently. 

The  edema  of  lymphatic  obstruction  has  a  characteristic  appearance.  There 
is  no  redness  or  cyanosis  of  the  skin,  and  having  attained  a  certain  moderate 
degree,  it  may  remain  at  that  level  for  long  periods.  This  corresponds  to  the 
mode  of  its  production.  Tissue  drainage  via  the  lymphatics  being  stopped,  the 
outflow  from  the  capillaries  will  equal  the  return  ilow  into  them,  and  there  will 
be  no  occasion  for  further  increase  of  tissue  fluid.  In  very  long-standing  lymph- 
edema the  skin  and  subcutaneous  tissues  are  apt  to  show  some  hypertrophy  and 
induration. 

There  are  many  conditions  in  which  lymphatic  obstruction  occurs.  Lymph- 
angitis may  cause  temporary  or  at  times  permanent  obliteration  of  lymph  chan- 
nels, or  they  may  become  occluded  by  invading  cancer  cells.  Surgical  removal  of 
groups  of  lymph  nodes  is  followed  often  by  regional  edema.  In  tropical  ele- 
phantiasis the  lymphatics  are  blocked  by  filaria.  In  addition  a  good  many 
cryptogenic  cases  of  lymphedema  are  seen^,  including  the  rare  familial  edema  of 
Milroy  and  a  group  of  somewhat  similar  sporadic  lymphedemas,  occurring  es- 
pecially in  women.  Some  of  these  are  believed  to  have  resulted  from  old  pelvic 
inflammatory  disease^^.  The  pathogenesis  is  not  known.  (See  also  Oxford 
Medicine,  Vol.  II,  Chapter  XIV-C,  Swellings  of  the  Limbs  due  to  Local  Causes.) 

Inflammatory,  Toxic  and  Allergic  Edemas 

The  presence  in  the  tissues  of  substances  toxic  to  the  vascular  and  tissue  cells 
produces  edema  regularly  as  a  part  of  the  reaction.  Burns,  bites,  chemical  irri- 
tants of  various  sorts  are  the  common  exciting  agents,  and  a  humoral  toxic  agent 
probably  is  active  also  in  tissues  that  are  especially  sensitive  to  allergic  antigens 
and  to  certain  physical  agents  such  as  heat,  cold  and  mechanical  stimulation. 
Common  to  all  of  these  reactions  is  an  early  hyperemia,  presumably  with  increased 
intracapillary  pressure  and  an  increased  permeability  of  the  capillary  wall  as 
evidenced  by  the  high  protein  content  of  the  edema  fluid.  The  cloudy  swelling 
of  inflammatory  tissue  cells  is  evidence  that  some  increase  in  the  volume  of  the 
cells  must  occur  also.  The  edema  that  may  persist  after  active  inflammation 
has  subsided  is  due  to  the  lowering  of  tissue  pressure  which  follows  stretching  of 
the  tissues. 

Of  particular  interest  is  the  group  of  skin  reactions  with  wheal  formation 
that  are  produced  by  heat,  chemical  irritants,  mechanical  stroking  and  probably 
at  times  by  neurogenic  impulses.  Lewis^^  has  presented  evidence  that  a  substance 
resembling  histamine  is  liberated  in  the  skin  in  response  to  each  of  these  agents, 
and  that  the  same  mechanism  is  common  to  the  action  of  all  of  them.  In  the 
^ase  of  remote  response  to  nerve  impulses  such  as  that  in  herues  zoster  and  some 
Vol.  I.  1 147 


I 


938  EDEMA 

urticarial  lesions  Dale^  has  suggested  that  Hberation  of  acetylcholine  at  the  ar- 
teriolar nerve  endings  may  play  a  role,  producing  both  vasodilatation  and  in- 
creased capillary  permeability.  There  is  a  large  group  of  cases  of  asthma,  urticaria 
and  angioneurotic  edema,  in  which  specific  allergy  may  not  be  demonstrable,  and 
in  which  psychic  and  nervous  influences  frequently  precipitate  the  attack.  In 
these  a  neurochemical  mechanism  seems  not  unlikely.  The  rare  local  edemas 
occurring  in  diseases  of  the  central  nervous  system  probably  would  belong  in 
the  same  group. 

The  Clinical  Investigation  of  Edema 

The  cause  of  most  edemas  can  be  determined  by  means  of  a  good  history  and 
physical  examination  and  a  routine  urine  analysis.  In  the  study  of  cases  of  ob- 
scure edema  the  following  measurements  may  be  of  value;  (i)  total  plasma 
protein  concentration,  (2)  fractionation  of  plasma  albumin  and  globulin,  (3)  col- 
loidal osmotic  pressure  of  plasma,  (4)  blood  volume,  (5)  blood  and  urine  chlorides, 
(6)  hematocrit  determination,  (7)  quantitative  protein  in  the  urine,  (8)  weight 
curve  of  patient,  (9)  venous  pressures. 

Fairly  satisfactory  clinical  methods  are  available  for  total  plasma  protein 
determinations  based  on  the  parallelism  between  protein  content  and  specific 
gravity^^.  Present  clinical  methods  for  albumin-globulin  fractionation  are  un- 
satisfactory but  may  be  of  some  value,  particularly  in  determining  changes  from 
time  to  time.  Colloid  osmotic  pressure  measurements  are  rarely  available  clini- 
cally, and  are  worth  little  unless  done  by  special  workers  Blood  volumes  usually 
are  determined  clinically  by  convenient  dye  methods,  whose  inaccuracies  are 
many  and  well  known.^^ 

BIBLIOGRAPHY 

1.  ADDIS,  T.:  Proteinuria,  Transact.  Assoc.  Am.  Phys.,  1942,  LVII,  106. 

2.  ADDIS,  T.:  Unpublished  observations. 

3.  ALLEN,  E.  v.:    Lymphedema  of  the  extremities,  Arch.  Int.  Med.  1934,  LIV,  60 

4.  BRIGHT,  R. :  Reports  of  Medical  Cases,  I,  83,  Longman,  Rees,  Orne,  Brown  and 

Green,  London,  1827. 

5.  BYROM,  F.  B.:  The  nature  of  myxedema,  Clin.  Science,  1934,  1,  273. 

6.  CHRISTIAN,  H.  A.:    Types  of  edema  and  their  treatment.  New  England  Med. 

Jour.,  1935,  CCXIV,  418. 

7.  CHRISTIAN*,  H.  A.:    Some  changing  views  about  edema  and  diuresis,  Canad. 

Med.  Assoc.  Jour.,  1937,  XXXVII,  29. 

8.  COLLER,  F.  A.,  DICK,  V.  S.  and  MADDOCK,  W.  B.:    Maintenance  of  normal 

water  exchange.  Jour.  Am.  Med.  Assoc,  1936,  CVII,  1522. 

9.  DALE,  H. :   Chemical  factors  in  control  of  circulation,  Lancet,  1929,  I,  1179. 
Vol.  I.  1147 


BIBLIOGRAPHY  939 

10.  DARROW,  D.  C:  Tissue  water  and  electrolyte,  Ann.  Rev.  Physiol.,  1944,  VI,  95. 

11.  DRINKER,  C.  K.  and  FIELD,  M.  E.:    Lymphatics,  Lymph  and  Tissue  Fluid, 

Williams  and  Wilkins,  Baltimore,  1933. 

12.  DRINKER,  C.  K.:    Pulmonary  Edema  and  Inflammation,  Harvard  University 

Press,  Cambridge,  Mass.,  1945. 

13.  ELLIS,  L.  B.:    The  causes  and  treatment  of  edema.  New  England  Jour.  Med., 

1 941,  CCXXIV,  1060. 

14.  ELLIS,  L.  B.  and  WEISS,  S.:    Edema  associated  with  cerebral  hemiplegia.  Arch. 

Neurol,  and  Psych.,  1936,  XXXVI,  362. 

15.  ELLIS,  L.  B.:   Hypoproteinemia  in  patients  with  cardiac  edema,  Med.  Clin.  North 

America,  1933,  XVI,  943. 

16.  EPSTEIN,  A.  A.:   Causation  of  edema  in  chronic  parenchymatous  nephritis,  Am. 

Jour.  Med.  Sci.,  191 7,  CLIV,  638. 

17.  GAMBLE,  J.  L.:  Extracellular  Fluid,  Harvard  Medical  School,  1941. 

18.  HARRISON,  T.  R.:  Failure  of  the  Circulation,  2nd.  edition,  Williams  and  Wilkins, 

Baltimore,  1939. 

19.  KAGAN,  B.  M.:    Estimation  of  the  total  protein  content  of  plasma.  Jour.  Clin. 

Invest.,  1938,  XVII,  373. 

20.  LANDIS,  E.  M.,  ANGEVINE,  M.  and  ERB,  W.:    Passage  of  fluid  and  protein 

through  capillary  wall,  Jour.  Clin.  Invest.,  1932,  XI,  717. 

21.  LANDIS,  E.  M.:    Capillary  pressure  and  capillary  permeability.  Physiol.  Reviews, 

1934,  XIV,  404. 

22.  LANDIS,  E.  M.,  BROWN,  E.,  FAUTEUX,  M.  and  WISE,  C:    Central  venous 

pressure  in  relation   to  cardiac   "competence",  blood  volume  and  exercise. 
Jour.  Clin.  Invest.,  1946,  XXV,  237. 

23.  LEWIS,  T.:   Clinical  Science,  Illustrated  by  Personal  Exj^eriences,  Shaw  and  Sons, 

London,  1934. 

24.  LUISADA,  A.:    Pathogenesis  of  paroxysmal  pulmonarv  edema.  Medicine,   1940, 

XIX,  475- 

25.  McMASTER,  P.  D.:   The  lymphatics  and  lymph  flow  in  the  edematous  skin,  Jour. 

Exp.  Med.,  1937,  LXV,  373. 

26.  PETERS,  J.  P.:   Body  Water,  Charles  C.  Thomas   Springfield,  Illinois,  1935. 

27.  PETERS,  J.  P.:   Water  exchange,  Physiol.  Rev.,  1944,  XXIV,  490. 

28.  RYTAND,  D.  A.:  Edema  with  hypoproteinemia.  Arch.  Int.  Med.,  1942,  LXIX,  251. 

29.  SCHADE,  H. :   Grundziige  der  Oedempathogenese,  Ergeb.  der  inn.  Med.  u.  Kinder- 

heilk.,  1926,  XXXIV,  i. 
29(a).  SMITH,  H.  W.:  The  excretion  of  water.  Bull.  N.  Y.  Acad.  Med.,  1947,  XXIII, 
177. 

30.  SODEMAN,  W.  A.  and  BURCH,  G.  E.:    The  tissue  pressure  in  subcutaneous 

edema.  Am.  Jour.  Med.  Sci.,  1937,  CXCIV,  846. 

31.  STARLING,  E.  H:   On  the  absorption  of  fluid  from  the  connective  tissue  spaces, 

Jour.  Physiol.,  1896,  XIX,  312. 

32.  STARLING,  E.  H.:   Fluids  of  the  Body,  Arnold  Constable,  London,  1909. 

33.  STEAD,  E.  A.,  Jr.  and  WARREN,  J.  V.:  The  protein  content  of  extracellular  fluid. 

Jour.  Clin.  Invest.,  1944,  XXIII,  283. 
Vol.  I.  1147 


940  EDEMA 

34.  THORN,  G.  W.,  Physiologic  considerations  in  the  treatment  of  nephritis,  New 

England  Med.  Jour.,  1943,  CCXXIX,  ^^. 

35.  THORN,  G.  W.  and  EMERSON,  K.,  Jr.:    Role  of  gonadal  and  adrenal  cortical 

hormones  in  the  production  of  edema,  Ann.  Int.  Med.,  1940,  XIV,  757. 

36.  THORN,  G.  W.,  NELSON,  K.  R.  and  THORN,  D.  W.:  A  study  of  the  mechanism 

of  edema  associated  with  menstruation.  Endocrinology,  1938,  XXII,  155. 

37.  WARREN,  J.  V.  and  STEAD,  E.  A.,  Jr.:    Edema  fluid  in  acute  nephritis.  Am. 

Jour.  Med.  Sci.,  1944,  CCVIII,  618. 

38.  WARREN,  J.  V.  and  STEAD,  E.  A.,  Jr.:    Fluid  dynamics  in  chronic  heart  failure, 

Arch.  Int.  Med.,  1944,  LXXIII,  138. 

39.  WARREN,  J.  v.,  MERRILL,  A.,  Jr.  and  STEAD,  E.  A.,  Jr.:   The  role  of  extra- 

cellular fluid  in  the  maintenance  of  plasma  volume,  Jour.  Clin.  Invest.,  1943, 
XXni,  635. 

40.  WEISS,  S.  and  WILKINS,  R.  W.:   Cardiovascular  disturbances  in  nutritional  de- 

ficiencies, Ann.  Int.  Med.,  1937,  XI,  104. 

41.  WELCH,  W.  H.:  Zur  Pathologie  des  Lungenodems,  Virch.  Arch.,  1878,  LXXII,  375. 

42.  WIDAL,  F.  and  JAVAL,  A.:  Les  variations  de  la  permeabilite  du  rein  par  la  chlo- 

rure  de  sodium  et  de  I'uree  dans  le  mal  de  Bright,  Compt.  rend.  Soc.  de  Biol, 
de  Paris,  1903,  LV,  1532. 

43.  WIGGERS,  C.  J.:    Physiology  in  Health  and  Disease,  4th  ed..  Lea  and  Febiger, 

Philadelphia,  1944. 

September  i,  1947. 


The  following  pages  will  be  used  at  a  later  date. 


Vol.  I.  1 147 


I 


I 


t 


CHAPTER  XXIV 


THE  RECiULATION  OF  BODY  WATER  AND 
ELECTROLYTE   IN   HEALTH  AND   DISEASE 

Bv  DANIEL  C.  HARROW  and  KDW  ARD  L.  PRATT 


Table  of  Contf.nts 

The  Relation  of  Extracellular  to  Intracellular  Electrolyte  942 

Metabolic  Acidosis         949 

Metabolic   Alkalosis 950 

Respiratory  Acidosis 951 

Respirat()r\'  Alkalosis 951 

Hypotonic  Dehydration 952 

Hypertonic  Deh\'dration 953 

Edema 954 

Changes  in  Tissue  Composition 955 

The  Expenditure  of  Water  and  Electrolyte 962 

Losses  from  Lungs  and  Skin 962 

Stool  Water 962 

Kidney   Excretion 963 

Summary         966 

Abnormal  Losses  of  Water  and  Electrolyte 967 

Sweat         967 

Gastrointestinal    Losses                   969 

Renal    Losses 972 

Vascular  Movements  of  Fluids 972 

Kidneys  in  Relation  to  Body  Fluids 973 

H\pokalieniia 986 

Hyperkalieniia 987 

Electrocardiograms  in  Hypo-  and  Hyper-kaliemia   ...  987 

Summary 988 

Bibliography 994 

Without  a  considerable  knowledge  of  the  physiology  of  body  water 

and  electrolyte,  physicians  cannot  properly  treat  dehydration,  edema, 

acidosis,  alkalosis  and  shock,  or  plan  a  rational  therapy  when  all  or  part 

COPYRIGHT    1952    BY    OXKOKl)    UXIVERSttY    PRESS,    INC. 

941 


942     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

of  the  fluid  requirement  must  be  given  parenterally,  or  electrolyte  has 
been  lost  in  large  amounts  in  sweat,  urine  and  gastrointestinal  secretions. 
Previous  concepts  of  the  physiology  of  body  fluids  were  dominated 
by  two  postulates  which  are  now  known  to  be  erroneous.  First,  cellular 
membranes  were  regarded  as  practically  impervious  to  sodium  and 
potassium,  and  second,  only  alterations  in  extracellular  electrolyte  were 
thought  to  be  accessible  to  fluid  therapy.  During  the  past  fifteen  years 
analyses  of  the  tissues  of  experimental  animals  and  detemiinations  of 
the  balances  of  water  and  electrolytes  in  patients  have  demonstrated 
that  intracellular  fluids  undergo  fairly  rapid  changes  in  composition 
which  alter  profoundly  the  acid-base  equilibrium  of  extracellular  fluids. 
Furthermore,  the  changes  in  composition  of  intracellular  fluids,  particu- 
larly the  loss  of  potassium  and  the  alterations  in  the  concentration  of 
electrolytes  in  body  fluid,  afl^ect  the  function  of  cells. 


The  Relation  of  Extracellular  to  Intracellular  Electrolyte 

In  order  to  enable  the  physician  to  visualize  the  quantitative  rela- 
tionships between  extracellular  and  intracellular  electrolyte,  a  schematic 
representation  of  the  composition  will  be  presented\  The  extracellular 
fluids  will  be  considered  to  have  the  composition  of  an  ultrafiltrate  of 
plasma.  The  intracellular  concentrations  will  be  represented  as  those 
of  rat  and  cat  muscle.  Both  concentrations  will  be  expressed  per  kilo- 
gram of  water.  Data  are  available  which  indicate  that  the  intracellular 
compositions  of  the  muscle  of  young  and  mature  cats  are  essentially  the 
same  and  that  human  muscle  has  about  the  same  composition  as  that  of 
other  mammals.  The  intracellular  composition  of  the  various  tissues  is 
similar  to  that  of  skeletal  muscle.  Some  of  the  changes  in  intracellular 
composition,  which  will  be  described,  are  known  not  to  develop  to  the 
same  extent  in  other  tissues,  but  similar  changes  probably  take  place. 
Since  the  intracellular  fluid  of  muscle  comprises  about  70  per  cent,  of 
the  total  intracellular  fluids,  the  errors  are  not  significant  in  depicting 
the  relationship  between  extracellular  and  intracellular  fluids  for  the 
body  as  a  whole. 

Charts  I  and  II  illustrate  the  relationships  of  extracellular  and  intra- 
cellular fluids  of  one  kilogram  of  tissue  in  babies  and  adults.  The  extra- 
cellular concentration  of  sodium  is  represented  on  the  ordinate  for 
extracellular  fluids,  while  the  intracellular  concentration  of  potassium 
is  represented  on  the  ordinate  for  intracellular  fluids.    The  abscissae 

Vol.  I.  152 


RELATION  OF  EXTRACELLULAR  TO  INTRA-  943 

CELLULAR  ELECTROLYTE 

indicate  the  volumes  of  water  in  each  kind  of  fluid.  1  he  amount  of 
extracellular  sodium  and  intracellular  potassium  is  indicated  by  the 
respective  areas.  The  amounts  of  the  various  electrolytes  contained  in 
each  compartment  are  indicated  by  the  concentrations  multiplied  by 
the  volumes. 

It  will  be  seen  that  total  water  per  kilogram  of  tissue  is  slightly 
greater  in  infants  than  in  adults.  For  the  first  months  of  life  extracellular 
water  in  infants  is  about  30  per  cent,  of  the  body  weight.  Although  the 
intracellular  water  of  adults  may  be  slightly  less  than  45  per  cent,  of 
the  body  weight,  this  figure  is  suitable  for  all  ages.  Actually,  the  total 
body  water  varies  appreciably  in  normal  individuals.  The  chief  differ- 
ences are  accounted  for  by  variations  in  the  proportions  of  fat.  Since 
fat  is  deposited  with  relatively  little  water,  fat  individuals  contain  rela- 
tively less  water  per  unit  of  weight.  However,  the  quantitative  relation- 
ships between  the  two  types  of  fluid  are  essentially  the  same  in  nomial 
individuals  except  for  the  variations  with  age. 

Since  the  changes  in  body  water  and  acid-base  equilibrium  are 
explained  chiefly  by  variations  in  water,  sodium,  potassium  and  chloride, 
the  discussion  will  emphasize  the  rtMe  of  these  constituents.  First,  the 
total  intracellular  sodium  is  about  7  mM  per  kilogram  and  approxi- 
mately equivalent  to  total  extracellular  bicarbonate  or  one  fourth  of 
the  total  extracellular  sodium  excluding  the  sodium  of  bone  salts"  ^  The 
sodium  in  bone  salts  need  not  be  considered  again,  since  this  sodium 
does  not  alter  the  sodium  available  to  the  rest  of  the  body  except  when 
bone  salts  are  being  deposited  or  removed.  This  factor  is  small  in  any 
short  period  since  there  is  i  niM  of  sodium  for  each  30  mM  of  calcium 
in  calcified  material. 

Normally,  intracellular  sodium  is  variable,  since  sodium  can  be 
transferred  from  intracellular  to  extracellular  fluids  and  vice  versa.  The 
charts  show  the  usual  high  normal  value  for  intracellular  sodium.  In 
normal  individuals  the  variations  are  chiefly  in  the  direction  of  lower 
values.  Since  the  transfer  between  the  two  phases  of  body  fluid  appar- 
ently is  accomplished  without  change  in  extracellular  chloride,  the 
effect  on  extracellular  fluids  is  to  alter  the  amount  of  sodium  available 
to  form  bicarbonate.  If  total  body  electrolyte  does  not  change,  transfer 
of  extracellular  sodium  to  intracellular  fluids  decreases  the  concentra- 
tion of  bicarbonate  in  extracellular  fluids,  and  transfer  of  intracellular 
sodium  to  extracellular  fluids  increases  the  concentrations  of  bicar- 
bonate in  extracellular  fluids.  Hence  the  shift  of  sodium  between  the 
Vol.  I.  152 


944    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 


two  compartments  is  an  important  mechanism  for  diminishing  the 
variations  in  extracellular  bicarbonate.  In  abnormal  conditions  changes 
in  the  distribution  of  sodium  explain  the  development  of  disturbances 
in  acid-base  equilibrium.  In  many  clinical  situations  this  mechanism 
functions  in  addition  to  the  usually  described  buffers  of  the  blood  and 
must  be  considered  in  the  explanation  of  the  effects  of  balances  of 


mM  per  L 
Na 


140 
120 
100 
80 
60 
40 
20 


EXTRA- 
CELLULAR 


28X0.25  =  7.0 

II2X0.25=28X) 

140X0.25=35.0 

4  XO.25=L0 


mM  pzr  L 
K 
INTRACELLULAR 


140 
120 
100 
80 
60 
40 
20 


HC03-^I0X0.45=4.5 
-  CI  -*4  X0.45=  1.8 
-Na— ►15X0.45=  6.7 
-K  —►157X0.45=70 


0.2      0.  I 


0. 


0.2      0.3      0.4 


WATER     IN     LITERS 

Chart  I.  Diaijnim  of  h<)d\  fluid  of  i  kilogniiii  of  tissue  in  infants.  The  concentra- 
rion  of  sodium  and  potassium  is  represented  on  tlie  ordinates  for  the  extracelkdar  and 
intracellular  fluids  respectively.  The  volumes  arc  represented  on  the  abscissae.  T  he 
total  contents  are  given  by  "Jie  concentration  multiplied  by  the  volumes. 

Vol..  I.  152 


RELATION  OK  EXTRACELLULAR  TO  INTRA- 
CELLULAR ELECTROLYTE 


945 


electrolyte  on  the  acid-base  equilihriuiii  and  the  distribution  of  body 
water. 

Second,  intracellular  potassium  in  normal  animals  may  be  about  lo 
per  cent,  lower  than  the  values  shown  on  the  charts.  This  variation 
may  occur  without  appreciable  alteration  in  body  water  or  acid-base 
equilibrium.    The  charts  show  the  high  normal  figure  since  this  is  the 


mM  per  L 
Na 


EXTRA- 


140 
120 
100 
80 
60 
40 
20 


28X0.20=  5.6 

112X0.20=22.4 

140X0.20  =  28.0 

4X0.20=  0.8 


mM  p^r  L 
K 

INTRACELLULAR 


40 
120 
100 
80 
60 
40 
20 


HCO3 -10X045=45 
CI  — 4X0.45=1.8 

-  Na— 15X0.45=6.7 
K — 157X0.45=70.0 


0.2       0.1 — 0 0.1       0.2      0.3 

WATER     IN    LITERS 


0.4 


Chart  II.     Diagran)  of  body  fluid  of   i   kilogram  of  tissues  in  adults  and  children. 
For  description,  sec  Ciiart  I. 

\'oL.  I.  1 52 


946    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

one  usually  found  in  rats  and  cats.  Changes  in  intracellular  potassium 
may  occur  without  detectable  changes  in  intracellular  sodium,  though 
there  usually  is  a  reciprocal  relation  between  intracellular  sodium  and 
potassium. 

Third,  under  abnormal  conditions  as  much  as  one  half  of  the  intra- 
cellular potassium  of  muscle  may  be  replaced  by  about  two  thirds  of 
the  equivalent  amount  of  sodium.  This  change  in  intracellular  electro- 
lyte was  first  discovered  in  rats  subjected  to  diets  low  in  potassium*  ^ 
or  receiving  repeated  injections  of  desoxycorticosterone  acetate"'  \  As 
will  be  pointed  out  later,  this  type  of  deficit  of  potassium  develops  as 
a  result  of  decreased  intake  of  potassium  and  increased  output  in  urine, 
stools,  gastrointestinal  secretions  and  sweat.  Deficit  of  potassium  may 
result  also  from  processes  leading  to  release  of  this  ion  from  the  cells. 

Fourth,  there  is  a  predictable  relationship  between  the  acid-base 
equilibrium  and  the  composition  of  muscle  under  certain  circumstances". 
Chart  III  shows  the  relationship  between  the  concentration  of  bicar- 
bonate in  serum  and  the  intracellular  sodium  and  potassium  of  157  grams 
of  fat-free  muscle  solids.  Since  this  amount  of  fat-free  solids  is  associated 
with  450  grams  of  intracellular  water,  the  chart  shows  the  intracellular 
composition  for  the  same  amount  of  intracellular  fluids  as  charts  I  and 
II  show  for  I  kilogram  of  tissue.  The  relationship  was  demonstrated  for 
rats  subjected  to  any  one  of  the  following  conditions:  (i)  loss  of 
chloride  or  primary  metabolic  alkalosis,  (2)  loss  of  sodium  or  primary 
metabolic  acidosis  and  (3)  primary  deficit  of  potassium.  Since  water 
and  other  ions  were  abundantly  available,  the  chart  is  based  on  condi- 
tions in  which  the  kidneys  would  adjust  body  water  and  electrolyte  to 
a  deficit  of  only  one  of  the  ions,  sodium,  potassium  or  chloride.  The 
relationship  may  be  regarded  as  a  biological  adjustment  or  steady  state 
for  these  conditions.  The  adjustment  must  be  considered  a  biological 
one  since  a  chemical  equilibrium  or  steady  state  would  be  achieved  in 
several  hours  and  not  require  several  days.  The  chart  is  useful  in  illus- 
trating the  sort  of  chang^es  which  the  body  will  tend  to  develop  with  a 
deficit  of  one  of  these  ions  when  the  kidneys  are  able  to  maintain  a 
relatively  constant  composition  of  the  body  fluids. 

The  chart  is  based  on  data  from  rats  where  the  relationship  is  readily 
demonstrated.  Clinical  studies  show  that  the  relationship  is  manifested 
in  humans.  In  dogs**  it  is  difficult  to  induce  alkalosis  in  response  to 
potassium  deficiency,  though  the  same  changes  in  cellular  composition 
result  from  deficit  of  potassium. 

It  will  be  seen  that  deficit  of  chloride  and  deficit  of  potassium  pro- 

VoL.  I.  152 


RELATION  OF  EXTRACELLULAR  TO  INTRA- 
CELLULAR ELECTROLYTE 


947 


duce  the  same  changes  in  both  extracelkilar  and  intracellular  fluids.  At 
biological  adjustment  a  deficit  of  one  of  these  ions  leads  to  deficit  of 
the  other.  Intracellular  sodium  may  reach  several  times  the  normal 
value  and  several  times  the  equivalence  of  the  bicarbonate  of  extra- 
cellular fluids.  This  relationship  is  important  first,  because  alkalosis  will 


RELATION  OF  SERUM   BICARBONATE    TO    INTRACELLULAR 
SODIUM  AND  POTASSIUM    \N   ONE   KILOGRAM    OF    TISSUE 

Serum  HCO3    mM  per   L 
15         20        25         30        35         40         45         50 

J I I i 1 1 1 1  Serum 

HCO3 


Cell 
K 

mM 
per 

I57gm 
Fa+- 
free 

Solids 


75  - 


70  - 


M 


pei 

L 


T r 

0  5  10  15  20  25  30 

In+racellular  Sodium  mM  per  i57gm  Fai-free  Solids 

Chart  III.  Relation  of  the  concentration  of  serum  bicarbonate  to  intracellular 
sodium  and  potassium  of  muscle.  The  line  shows  the  relation  of  intracellular  sodium  to 
potassium;  the  bicarbonate  concentrations  on  the  ordinate  are  the  best  fit  for  intracellular 
potassium,  while  those  on  the  abscissae  are  the  best  fit  for  the  intracellular  sodium.  The 
values  for  intracellular  sodium  and  potassium  are  for  the  same  amount  of  intracellular 
fluid  used  for  i  kilogram  of  tissue  in  Charts  I,  II  and  IV. 

Vol.  L  152 


948     REGULATION  OF  BODY  WATER  AND  ELECTROL^  TE 

tend  to  persist  if  potassium  cannot  be  replaced,  and  second,  because 
deficit  of  potassium  will  result  in  alkalosis  even  in  the  presence  of 
abundant  sodium  chloride.  Examples  of  both  of  these  events  will  be 
cited  later.  On  the  other  hand  acidosis  produced  by  loss  of  sodium 
alone  leads  to  deficits  of  this  ion  not  only  in  the  extracellular  fluids  but 
also  in  the  cells.  It  is  this  combined  deficit  that  measures  the  amount 
of  sodium  bicarbonate  that  must  be  retained  in  order  to  restore  the 
concentration  of  bicarbonate  in  serum.  Thus  acidosis  resulting  from 
loss  of  sodium  without  loss  of  potassium  will  have  an  extracellular 
deficit  equal  to  the  decrease  in  bicarbonate  concentration  multiplied  by 
the  volume  of  extracellular  water,  i.e.  (25—5)  0.2  5  =  5  mM  of  sodium 
per  kilogram  of  body  weight,  if  the  serum  bicarbonate  is  5  mM  per 
liter.  In  addition,  there  would  be  a  deficit  of  about  7  mM  of  sodium  in 
the  cells  making  a  total  deficit  of  about  1 2  mM  per  kilogram  of  body 
weight. 

Clinically,  chloride  is  relatively  deficient,  if  the  concentration  in 
serum  is  low,  but  the  loss  may  occur  alone  or  in  conjunction  with 
deficit  of  potassium  or  as  a  result  of  deficit  of  potassium.  Low  concen- 
tration of  bicarbonate  indicates  a  loss  of  sodium  from  extracellular 
fluids  unless  there  is  an  accumulation  of  other  ions  displacing  bicar- 
bonate. However,  the  decrease  in  bicarbonate  does  not  reveal  the  state 
of  intracellular  sodium,  since  if  there  is  deficit  of  potassium,  there  may 
be  high  intracellular  sodium  in  the  presence  of  acidosis.  Deficit  of 
potassium  can  be  proved  only  by  demonstrating  a  greater  relative  loss 
of  potassium  than  nitrogen  during  the  development  of  the  condition  or 
a  greater  relative  retention  of  potassium  than  nitrogen  during  recovery. 
If  body  water  and  circulation  are  relatively  normal,  deficiency  of 
potassium  is  likely  to  be  accompanied  by  low  concentration  of  potas- 
sium in  serum. 

The  physiochemical  factors  controlling  the  acid-base  equilibrium 
of  the  blood  have  been  discussed  adequately  in  a  recent  paper  by  Singer 
and  Hastings''  and  in  textbooks'".  The  present  discussion  will,  there- 
fore, emphasize  the  relationship  of  the  changes  in  acid-base  equilibrium 
of  the  blood  to  alterations  in  the  composition  of  extracellular  fluids  and 
the  accompanying  changes  in  the  cells. 

Changes  in  the  acid-base  equilibrium  may  be  defined  as  deviations 
from  normal  in  the  reaction  or  pH  of  the  blood.  The  pH  is  determined 
by  the  ratio  of  the  carbon  dioxide  to  the  bicarbonate  of  plasma.  The 
concentration  of  carbon  dioxide  depends  on  the  partial  carbon  dioxide 
pressure   of  arterial   blood   which   is  normally   equilibrated   with   the 

Vol.  I.  152 


RELATION  OF  EXTRACELLULAR  TO  IN  LRA-  949 

CELLULAR  ELECTROLYTE 

carbon  dioxide  of  residual  alveolar  air.  Llence,  the  carbon  dioxide 
tension  is  subject  to  the  regulation  of  pulmonary  ventilation  by  the 
respiratory  center.  The  concentration  of  bicarbonate  in  plasma  is 
dependent  on  the  amount  of  cations  available  to  form  bicarbonate  at 
the  particular  carbon  dioxide  tension  with  the  particular  amounts  of 
blood  electrolytes  and  organic  buifers.  The  cations  available  to  form 
bicarbonate  are  regulated  bv  the  kidneys.  Inasmuch  as  we  are  chiefly 
concerned  with  the  content  of  water  and  electrolyte  in  body  fluids,  we 
shall  neglect  the  relatively  small  changes  in  the  buffering  effects  of  the 
plasma  proteins,  red  cells  and  phosphate  and  emphasize  the  contents 
of  the  tissues  in  sodium,  potassium  and  chloride.  These  ions  are  the 
chief  factor  determining  the  major  clinical  disturbances  in  the  amount 
of  cations  available  to  form  bicarbonate.  The  cations  available  to  form 
bicarbonate  are  the  algebraic  sum  of  the  total  cations  minus  the  plasma 
anions     excluding     bicarbonate,     i.e.     (Na  +  K  +  Ca  +  Mg)  —  (CI  + 

HPO4  +  proteins  +  sulphate  +  lactate  +  keto  acids ).  For  many 

purposes  the  changes  in  cations  available  to  form  bicarbonate  in  the 
body  as  a  whole  are  adequately  defined  by  the  balances  of  sodium  plus 
potassium  minus  chloride. 

Mctiiholic  Acidosis 

Metabolic  acidosis  is  primary  decrease  in  the  cations  available  to 
form  bicarbonate.  It  may  be  produced  by  relative  increase  in  the  con- 
centration of  anions  or  relative  decrease  in  the  concentration  of  cations. 
An  increase  in  anions  may  arise  as  a  result  of  ingestion  of  acidifying 
salts  or  through  the  endogenous  production  of  organic  acids  owing  to 
exercise,  anoxia,  hemorrhage,  keto  acids  in  starvation  ketosis  and 
diabetic  acidosis  or  the  retention  of  phosphates  and  sulphate  in  renal 
insufficiency.  A  relative  deficit  of  cations  may  result  from  losses  of 
intestinal  secretions,  biliary  secretions  or  through  abnormal  renal 
excretion. 

The  changes  in  intracellular  electrolytes  in  metabolic  acidosis  are 
only  beginning  to  be  studied.  Deficit  of  sodium  alone,  such  as  is  illus- 
trated in  chart  III,  apparently  is  relatively  rare.  It  has  been  shown  that 
feeding  protein  milk  to  premature  infants  leads  to  retention  of  chloride 
and  little  change  in  body  sodium"'  ^-'  'I  The  change  in  the  acid-base 
equilibrium  and  the  balances  demonstrates  that  practically  all  the  intra- 
\'oL.  1.  152 


950    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

cellular  sodium  is  transferred  to  the  extracellular  fluids  under  these 
circumstances.  The  resulting  change  in  intracellular  composition  must 
be  about  the  same  as  is  illustrated  for  deficit  of  sodium  in  chart  III. 
Acidifying  salts  such  as  ammonium  chloride  and  calcium  chloride  prob- 
ably produce  similar  changes.  In  one  baby  subjected  to  protein  milk 
feeding  for  six  days,  the  balances  showed  losses  of  intracellular  potas- 
sium during  the  last  three  days.  It  is  likely  that  acidosis  resulting  from 
loss  of  sodium  first  leads  to  deficits  f)f  sodium  in  the  extracellular 
and  intracellular  fluids  and  later,  losses  of  potassium  may  develop. 
Under  these  circumstances  sodium  may  be  transferred  back  into  the 
cells  and  aggravate  the  acidosis.  Thus  acidosis  beginning  as  primary 
sodium  deficit  tends  ultimately  to  produce  depletion  of  potassium 
and  water. 

Metabolic  acidosis  usually  is  accompanied  by  deficits  of  water, 
sodium,  potassium  and  chloride.  When  there  is  acidosis  and  deficit  of 
potassium,  intracellular  sodium  apparently  remains  normal  or  may  even 
be  somewhat  high  but  not  as  high  as  when  there  is  a  similar  deficit  of 
potassium  and  no  acidosis.  The  difi^erence  between  the  deficits  of 
sodium  and  potassium  and  the  deficit  of  chloride  is  a  measure  of  the 
relative  deficiency  of  cations  available  to  form  bicarbonate.  Since  the 
deficit  of  potassium  may  be  greater  than  total  normal  extracellular 
bicarbonate  plus  normal  intracellular  sodium,  most  cases  of  acidosis 
cannot  be  treated  rationally  with  sodium  chloride  and  sodium  bicar- 
bonate alone.  If  intracellular  potassium  remains  low,  the  amount  of 
sodium  in  excess  of  chloride  required  to  restore  extracellular  bicar- 
bonate would  be  more  than  the  normal  excess  of  sodium  over  chloride 
including  intracellular  sodium.  The  changes  in  tissue  composition  in 
metabolic  acidosis  indicate  clearly  that  replacement  of  potassium  as 
well  as  sodium  and  chloride  is  necessary  in  most  cases. 


Metabolic  Alkalosis 

Metabolic  alkalosis  is  produced  by  primary  increase  in  sodium  avail- 
able to  form  bicarbonate  in  plasma.  Although  metabolic  alkalosis  may 
be  produced  by  relative  excess  of  sodium,  it  usually  results  from  relative 
deficit  of  chloride.  The  commonest  cause  is  loss  of  gastric  juice  by 
vomiting  or  suction  drainage  after  operations.  If  sufficient  water  is 
available  to  permit  renal  adjustment,  potassium  will  tend  to  be  lost  from 
the  cells,  and  sodium  will  partially  replace  the  intracellular  deficit  of 

Vol.  I.  152 


RELATION  OF  EXTRACELLULAR  TO  INTRA-  951 

CELLULAR  ELECTROLYTE 

potassium.  If  the  plan  of  therapy  offers  no  opportunity  for  the  body 
to  replace  the  deficiency  of  potassium,  alkalosis  may  continue  despite 
the  administration  of  sodium  chloride,  because  the  biological  adjustment 
to  deficit  of  potassium  leads  to  maintenance  of  alkalosis  by  the  kidneys. 
A  similar  reaction  by  the  kidneys  explains  the  development  of  alkalosis 
as  a  result  of  primary  deficiency  of  potassium.  In  either  case  recovery 
from  alkalosis  requires  the  replacement  of  potassium  as  well  as  chloride. 

Respiratory  Acidosis 

Respiratory  acidosis  results  from  primary  increase  in  serum  carbon 
dioxide  tension.  Probably  the  most  frequent  cause  is  depression  of 
pulmonary  ventilation  owing  to  narcosis,  injury  to  the  respiratory 
center  or  paralysis  of  the  muscles  of  respiration.  However,  both  acute 
and  chronic  respiratory  acidosis  may  be  produced  by  diseases  of  the 
lun^s  leading  to  thickening  of  the  alveolar  walls,  exudates,  bronchiec- 
tasis and  emphysema.  Since  oxygen  diffuses  less  rapidly  than  carbon 
dioxide,  the  arterial  blood  becomes  less  saturated  with  oxygen  than 
normal  when  carbon  dioxide  accumulates.  Presumably,  there  is  no 
change  in  body  electrolyte  in  uncompensated  respiratory  acidosis. 

Respiratory  Alkalosis 

Respiratory  alkalosis  results  from  primary  decrease  in  carbon  diox- 
ide tension.  It  is  produced  by  excessive  pulmonary  ventilation  such  as 
occurs  during  exercise,  fever  and  disturbances  in  the  respiratory  center 
as  a  result  of^infections  of  the  central  nervous  system,  tumors  and  drugs 
(salicylates).  Overventilation  may  occur  in  hysterical  patients  or  as 
a  result  of  anoxia  in  cardiac  failure  and  at  high  altitudes.  Uncompen- 
sated respiratory  alkalosis  presumably  results  in  no  change  in  body 
electrolytes. 

The  disturbances  in  acid-base  eqwUbriiuji  have  been  discussed  above 
as  if  only  the  carbon  dioxide  tension  or  the  cations  available  to  form 
bicarbonate  were  altered.  Actually  the  alteration  of  one  of  these  vari- 
ables leads  to  compensatory  variations  in  the  others.  In  metabolic  aci- 
dosis the  respiratory  center  responds  to  the  low  pH  by  increased 
pulmonary  ventilation  which  reduces  the  carbon  dioxide  tension.  The 
reduction  is  not  sufficient  to  produce  a  normal  pH  in  the  blood.    In 

Vol.  I.  152 


952     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

metabolic  alkalosis  the  respiratory  center  may  reduce  pulmonary  ven- 
tilation, but  the  reaction  is  limited  because  anoxia  tends  to  be  produced 
and  again  stimulates  increased  respirations. 

On  the  other  hand,  the  kidneys  may  alter  the  cations  available  to 
form  bicarbonate  in  both  respiratory  acidosis  and  alkalosis.  In  respira- 
tory alkalosis  the  serum  bicarbonate  may  be  reduced  fairly  rapidly,  but 
as  long  as  the  disturbance  in  pulmonary  ventilation  persists,  the  blood 
pH  remains  normal  or  slightly  alkaline.  However,  after  the  kidneys 
have  reduced  the  available  cations,  the  respiratory  center  may  recover 
and  respond  normally.  The  patient  then  will  suffer  from  true  metabolic 
acidosis.  Since  recovery  from  the  effects  of  drugs  such  as  salicylates 
may  be  rather  rapid,  respiratory  alkalosis  is  likely  to  go  through  a  phase 
of  metabolic  acidosis  during  recovery. 

In  respiratory  acidosis  the  kidneys  may  increase  the  cations  available 
to  form  bicarbonate  to  quite  high  figures  (45  miM  per  liter).  The  blood 
pH  remains  more  acid  than  normal,  and  arterial  blood  shows  diminished 
oxygen  saturation.  In  respiratory  acidosis  due  to  lung  disease  recovery 
of  lung  function  is  unlikely  to  be  sufficiently  rapid  to  produce  true 
metabolic  alkalosis. 

It  is  not  known  M^hethcr  compensated  respiratory  alkalosis  and 
acidosis  lead  to  changes  in  cell  sodium  and  potassium.  It  is  likely  that 
such  is  the  case  and  that  compensated  respiratory  acidosis  produces 
increase  in  cell  sodium  and  decrease  in  cell  potassium.  Compensated 
respiratory  alkalosis  is  likely  to  lead  to  loss  of  intracellular  as  well  as 
extracellular  sodium. 

Disturbances  in  body  water  and  electrolyte  involve  changes  in  the 
volume  and  electrolyte  concentration  which  are  just  as  important  as 
the  changes  in  acid-base  equilibrium.  Dehydration  usually  involves 
decrease  in  body  electrolyte,  and  loss  of  electrolyte  tends  to  cause  losses 
of  water.  If  the  losses  of  electrolyte  are  proportionately  greater  than 
the  losses  of  water,  there  is  a  decrease  in  the  concentration  of  electrolyte 
in  scrum.  This  type  of  disturbance  may  be  called  hypotonic  dehy- 
dration. 

Hypotonic  Dehydration 

Methods  are  available  for  study  hypotonic  dehydration  due  to 
loss  of  electrolyte  with  little  change  in  body  water^\  Loss  of  extra- 
cellular electrolyte  without  significant  change  in  body  water  produces 
decrease  in  the  concentration  of  sodium  and  chloride  in  serum,  while 

\oi^  I.  152 


RELATION  OF  EXTRACELLULAR  TO  INTRA-  9^-; 

CELLULAR  ELECTROLYTE 

the  concentration  of  proteins  in  serum  and  red  cells  in  blood  are  in- 
creased. The  plasma  volume  is  markedly  reduced.  The  animals  look 
sick,  refuse  to  eat  and  are  weak.  The  volume  of  urine  decreases,  the 
rate  of  glomerular  filtration  is  reduced  to  quite  low  figures,  the  non- 
protein nitrogen  rises.  Water  and  sodium  are  excreted  more  slowly 
than  normal''.  The  cardiac  output  is  strikingly  reduced'".  It  can  be 
shown  that  the  volume  of  extracellular  water  decreases  while  the 
volume  of  intracellular  water  increases.  The  changes  in  distribution 
of  water  are  dependent  on  the  adjustment  of  the  osmotic  pressure  in 
the  intracellular  fluids  by  shifts  of  water  rather  than  by  losses  of  elec- 
trolyte from  the  cells.  The  animals  are  in  a  shock-like  state  and  do  not 
withstand  bleeding  as  well  as  normal  animals'".  The  clinical  picture  is 
essentially  the  same  as  that  of  the  usual  dehydration  seen  in  patients. 
The  experiments  are  important  because  they  emphasize  that  the  central 
feature  of  hypotonic  dehydration  is  loss  of  extracellular  electrolyte. 
For  practical  purposes  hypotonic  dehydration  may  be  considered 
to  result  from  the  loss  of  proportionately  more  electrolyte  than  water, 
although  rare  cases  may  involve  little  or  no  deficit  of  water.  With  low 
concentrations  of  electrolyte  in  serum  the  cells  of  the  body  contain  more 
water  than  is  normal.  Statistically  the  increase  in  intracellular  water 
in  experiments  involving  losses  of  extracellular  electrolytes  is  only  about 
two  thirds  as  much  as  would  reduce  the  electrolyte  concentration  of  the 
intracellular  fluids  of  muscle  as  much  as  the  reduction  of  extracellular 
concentration'\  In  chronic  states  in  patients  the  relationship  has  not 
been  studied  but  may  be  somewhat  different.  In  any  case  the  disturb- 
ances in  circulation,  renal  function  and  muscular  strength  are  dependent 
not  only  on  the  reduction  in  extracellular  water  and  plasma  volume  but 
also  on  tile  decrease  in  electrolyte  concentration'".  Hypotonic  dehydra- 
tion produces  the  picture  of  medical  shock  and  responds  to  replacement 
of  electrolyte,  but  the  response  is  somewhat  better  when  blood  or 
plasma  as  well  as  electrolyte  is  given'". 


Hy  per  tonic  Deby  drat  ion 

Hypertonic  dehydration  results,  when  the  loss  of  water  is  propor- 
tionately greater  than  the  loss  of  electrolyte.    This  leads  to  increase  in 
the  concentration  of  electrolyte  in  serum'".   It  can  be  shown  that  rela- 
tively pure  increase  in  extracellular  electrolyte  produces  increase   in 
Vol..  1.  152 


954    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

extracellular  water  and  dehydration  of  the  cells".  Patients  with  hyper- 
tonic dehydration  may  show^  symptoms  of  shock,  but  circulatory  failure 
is  much  less  prominent  than  in  hypotonic  dehydration.  The  patients 
are  likely  to  show  hyperpnea,  mental  symptoms  and  fever-".  Patients 
and  experimental  animals  with  hypertonic  fluids  show  evidence  of 
cerebral  damage;  death  is  likely  to  be  preceded  by  high  fever  and 
arrest  of  respiration. 

As  will  be  pointed  out  later,  symptoms  develop  when  serum  potas- 
sium rises  to  about  twice  the  normal  concentration.  When  the  level  of 
serum  potassium  increases,  the  concentration  of  potassium  in  cells  rises\ 
However,  if  animals  are  given  diets  high  in  potassium,  the  compositions 
of  the  cells  remain  essentially  normal.  If  rats  are  given  water  containing 
potassium  chloride  at  greater  concentrations  than  can  be  excreted  by 
the  kidneys,  they  refuse  to  drink.  If  potassium  chloride  is  injected  into 
the  peritoneal  cavity,  the  concentration  in  the  serum  rises  in  proportion 
to  the  amount  injected.  Accompanying  this  rise  there  is  an  increase  in 
the  intracellular  potassium.  If  the  potassium  does  not  produce  fatal 
intoxication  in  60  to  90  minutes,  the  rats  survive.  If  they  Hve  for  about 
18  hours,  compensatory  excretion  leads  to  low  nomial  potassium  in  the 
muscle.  From  these  facts  it  can  be  seen  that  high  intracellular  potassium 
probably  does  not  occur  except  when  extracellular  potassium  is  also 
high. 

Edevm 

The  term  edema  should  be  limited  to  expansion  of  extracellular 
water  and  electrolytes.  As  will  be  pointed  out  later,  edema  may  develop 
from  disturbances  in  the  exchange  between  the  capillaries  and  inter- 
stitial fluids.  However,  the  large  expansions  of  extracellular  fluids  are 
accompanied  by  evidences  of  failure  of  the  kidneys  to  excrete  sodium. 
The  expansion  of  water  in  extracellular  fluids  may  be  so  great  that  half 
of  the  body  weight  is  extracellular.  The  edema  may  be  accompanied 
by  acidosis,  alkalosis  or  low  electrolyte  concentrations.  Although  in- 
crease in  electrolyte  concentration  usually  leads  to  further  expansion  of 
body  fluids  so  as  to  reduce  the  electrolyte  concentrations,  hypertonic 
concentration  may  be  found  in  edematous  patients.  \\'hile  the  actual 
composition  of  the  intracellular  fluids  in  the  presence  of  edema  has 
not  been  studied,  it  is  usually  assumed  that  the  intracellular  structures 
are  well  preserved.  However,  there  is  no  reason  to  doubt  that  the  cells 
undergo  the  same  sort  of  changes  in  composition,  when  the  concentra- 
VoL.  I.  152 


RELA.TION  OF  EXTRACELLULAR  TO  INTRA-  955 

CELLULAR  ELECTROLYTE 

tions  and  acid-base  cquilibriuni  of  the  plasma  are  altered,  as  has  been 
shown  to  be  the  case,  when  there  is  no  increase  in  extracellular  volume. 
Thus,  hypotonic  edema  should  produce  increased  hydration  of  the  cells, 
while  hypertonic  edema  should  lead  to  dehydration  of  the  cells.  There 
is  also  evidence  that  low  electrolyte  concentration  in  patients  with 
edema  leads  to  circulatory  failure  similar  to  that  seen  in  hypotonic 
dehydration.  Renal  function  and  circulation  may  be  improved  by 
raising  the  electrolyte  concentration  by  giving  sodium  chloride  and 
sodium  bicarbonate!  It  is  likely  that  some  of  the  cases  of  edema  show 
the  chani^cs  in  intracellular  composition  illustrated  in  chart  III,  when 
there  is  a  disturbance  in  bicarbonate  concentrations  produced  by  a 
primary  relative  deficiency  of  one  ion. 


Changes  in  Tissue  Composition 

With  the  above  background,  based  largely  on  studies  of  experimen- 
tal animals,  the  changes  in  tissue  composition  in  certain  conditions  in 
patients  will  be  discussed  briefly.  It  must  be  realized  that  actual  values 
for  patients  are  difficult  to  obtain,  and  that  the  methods  are  subject  to 
errors  not  involved  in  tissue  analyses.  The  composition  of  tissue  of 
patients  can  be  inferred  by  measuring  the  losses  during  development  of 
the  disturbance  or  by  measuring  the  retentions  during  recovery.  Since 
it  has  seldom  been  possible  to  determine  the  skin  losses,  the  balances 
usually  are  incomplete.  However,  this  lack  of  complete  balance  does 
not  preclude  approximate  estimations  of  the  changes  in  body  com- 
position. 

The  experiments  on  animals  indicate  that  the  magnitude  of  the 
losses  of  extracellular  electrolyte  in  patients  probably  never  is  greater 
than  one  third  of  the  normal  content,  i.e.  about  9  mEq  of  CI  and  12 
niEq  of  Na  per  kilogram  of  body  weight  in  babies  or  6  and  10  in  adults. 
This  conclusion  is  based  on  the  fact  that  losses  that  are  this  great  in 
cats  and  dogs  lead  to  symptoms  that  simulate  those  seen  in  the  sickest 
patients.  Loss  of  half  of  the  extracellular  electrolyte  apparently  was 
more  than  the  animals  could  withstand' \  The  experiments  on  potassium 
deficiency  in  animals  indicate  that  only  as  much  as  half  of  the  potassium 
of  muscle  may  be  replaced  by  sodium.  Neglecting  deficits  in  other 
tissue,  this  would  indicate  that  the  maximum  deficit  of  potassium  could 
Vol.  I.  152 


956    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

be  about  24  niM  per  kilogram  of  body  weight.   It  is  unlikely  that  values 
greater  than  17  \\ill  be  found  in  patients. 

liijiWtile  durrrl?ea  produces  deficits  of  water,  sodium,  potassium  and 
chloride  which  show  considerable  variations  in  the  absolute  and  relative 


m  M  pzr  L 
Na 


140 
120 
100 
80 
60 
40 
20 


EXTRA- 
CELLULAR 


18X017=  3p^ 
112X0.(7=19  ^ 
130X0.17=22  " 
5X0.17=0.85 


HCO3 
-CI- 
-Na 
—  K- 


HOX0.37  =  3.7 
^5X0.37=L8 
39.6X0.37=10.7 
162X0.37=60 


100 
80 
60 
40 
20 


0.2      0.1  ^<— 0— ►O.I        0.2      0.3    0.4 
WATER    IN    LITERS 

Chart  I\\     Diagnini  of  i   kilogram  of  tissue  in  infantile  diarrhea.    The  deficits  arc 
115  gni.  of  water,  g  ni.M  of  chloride,  9  m.M  of  sodiiini  anil   10  ni.M  of  potassium. 

losses  of  these  constituents.  The  plasma  may  be  hypotonic  or  hyper- 
tonic. Metabolic  acidosis  usually  is  present  in  the  severe  cases.  The 
balances  during  recovery  in  8  severe  cases  sho\\'ed  average  retentions 
per  kilogram  of  body  weight  of  125  grams  of  water,  9.2  mi\l  of  chloride, 
\'()i..  1.  152 


RELAllON  OF  EX  IRACLLLULAR    lO  IMRA-  9^-7 

CELLULAR  ELECTROLYTE 

9.5  niAl  of  sodium  and  10  niM  of  potassium.  Ihe  effect  of  such  deficits 
on  the  body  composition  of  a  normal  infant  is  sho^n  in  chart  IV.  Since 
the  deficiency  of  sodium  for  tlie  body  as  a  whole  is  equivalent  to  the 
deficiency  of  chloride,  the  acidosis  is  explained  by  transfer  of  extra- 
cellular sodium  to  the  cells.  This  conclusion  is  evident  from  the  fact 
that  the  low  concentration  of  bicarbonate  indicates  relative  deficiency 
of  sodium  in  extracellular  fluids. 

The  deficiency  of  potassium  is  equivalent  to  about  one  seventh  ol 
the  total  estimated  intracellular  potassium  content  of  normal  babies  or 
to  about  the  equivalent  of  one  fourth  of  the  normal  extracellular  sodium. 
Althouc^h  intracellular  sodium  is  abnormally  high,  the  intracellular 
sodium  is  not  as  great  as  the  deficit  of  potassium  would  predict  in  chart 
III.  1  he  deficiency  of  potassium  is  sufficient  to  explain  the  acidosis  devel- 
oping^ with  no  relative  deficit  of  sodium  in  relation  to  chloride.  The 
acidosis  in  infantile  diarrhea  is,  therefore,  dependent  on  deficit  of  potas- 
sium occurring  in  patients  with  deficiency^  of  water,  sodium  and 
chloride. 

The  studies  do  not  siiow  the  actual  changes  in  tissue  composition 
in  infantile  diarrhea,  since  the  state  of  nutrition  of  the  patients  usually 
is  greatly  disturbed.  The  older  literature  showed  that  babies  dying  of 
diarrhea  have  a  great  loss  of  intracellular  structures  which  apparently 
leave  extracellular  fluids  relatively  large  in  relation  to  body  weight''. 
However,  the  authors  have  analyses  of  muscles  that  confirm  the  changes 
in  intracellular  composition  indicated  by  the  balance  studies.  Since  the 
diagram  is  based  on  the  estimated  losses  subtracted  from  a  hypothetical 
normal  composition,  it  does  not  indicate  the  changes  in  tissue  composi- 
tion that  are  produced  by  undernutrition.  The  diagram  should,  there- 
fore, be  considered  to  represent  the  composition  only  in  a  well-nour- 
ished baby  with  acute  diarrhea.  The  deficit  of  extracellular  water  and 
electrolyte  is  about  one  fourth  of  the  normal  content.  Intracellular 
sodium  is  about  double  the  normal  value.  1  he  deficit  of  water  in  tlie 
cells  is  a  little  greater  than  that  of  extracellular  fluids. 

Inspection  of  the  diagram  enables  one  to  visuali/,e  the  results  of 
various  types  of  treatment.  If  the  infants  are  treated  with  sodium 
chloride  and  water  alone,  the  deficit  of  potassium  will  persist  and  sodium 
will  enter  the  cells  owing  to  persistence  of  the  deficiency  of  potassium". 
If  sufficient  water  is  available  to  permit  renal  adjustment,  high  intra- 
cellular sodium  and  low  intracellular  potassium  leads  to  alkalosis.  High 
concentration  of  bicarbonate  in  serum  also  aggravates  the  tendency  to 
\'oL.  I.  152 


958    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

development  of  low  serum  Ciilcium".  All  these  disturbances  will  dis- 
appear when  food  with  its  high  content  of  potassium  can  be  absorbed. 
Indeed  the  success  of  treatment  with  solutions  containing  sodium 
chloride  and  sodium  bicarbonate  depends  on  sufficiently  rapid  recovery 
to  permit  feeding. 

If  sodium  chloride  is  given  with  insufficient  water  to  permit  renal 
adjustment,  acidosis  may  persist  or  be  aggravated.  Case  3  of  a  previous 
study  illustrates  this  course  of  events"^  The  patient  was  admitted  for 
severe  diarrhea  which  had  been  treated  at  home  by  the  addition  of 
small  amounts  of  sodium  chloride  to  a  milk  mixture  that  gave  too  little 
water  for  a  baby  with  diarrhea.  On  admission  the  concentrations  of 
bicarbonate  and  chloride  in  serum  were  respectively  7  and  1 2  3  mM  per 
liter.  During  recovery  no  sodium  and  chloride  were  retained  while  13 
mM  of  potassium  and  100  gm.  of  water  per  kilogram  of  body  weight 
were  added  to  the  body.  Since  the  diarrhea  would  have  led  to  losses 
of  sodium  and  chloride  at  home,  if  sodium  chloride  had  not  been  added 
to  the  food,  this  treatment  had  prevented  deficits  of  these  ions.  The 
acidosis  probably  had  been  aggravated  by  transfer  of  sodium  to  the 
cells  since  sufficient  water  was  not  available  to  permit  renal  adjustment. 
The  persistent  deficit  of  potassium  explains  the  transfer  of  sodium  to 
the  cells.  On  entry  into  the  hospital  the  patient  suffered  chiefly  from 
deficit  of  water  and  potassium  leading  to  acidosis  and  hypertonic  dehy- 
dration. The  picture  was  the  result  of  treating  diarrhea  with  sodium 
chloride  and  insufficient  water.  A  similar  picture  is  seen  frequently 
when  acidosis  is  treated  with  saline  and  insufficient  water  free  of  elec- 
trolytes. 

Adults  ivith  diarrhea  have  not  been  studied  by  methods  which  dem- 
onstrate the  actual  deficits  of  water  and  electrolye.  Nevertheless,  it 
has  long  been  known  that  adults  lose  large  amounts  of  water,  sodium, 
potassium  and  chloride  in  dysentery  and  cholera-^  The  importance  of 
losses  of  potassium  is  indicated  by  the  observation  of  paralysis  following 
the  treatment  of  cholera'\  This  paralysis  was  relieved  by  the  intra- 
venous injection  of  potassium  chloride.  Similar  observations  have  been 
made  in  sprue-".  There  can  be  little  doubt  that  diarrhea  in  adults  leads 
to  striking  deficits  of  potassium  as  well  as  of  sodium  and  chloride  and 
water  and  that  the  changes  in  tissue  composition  are  similar  to  those  of 
infants. 

About  twenty  years  ago  Atchley  and  others^'  showed  that  diabetic 
acidosis  is  associated  with  losses  of  potassium  as  well  as  sodium  and 
chloride.    Holler  and  others"*-  -"■  ^^  observed  paralysis  during  recovery 

Vol.  I.  152 


RELATION  OF  EXTRACELLULAR  TO  INTRA-  959 

CELLULAR  ELECTROLYTE 

which  was  accompanied  by  low  concentrations  of  potassium  in  serum 
and  was  relieved  by  potassium  salts.  The  authors  found  that  the  reten- 
tions during  recovery  in  a  severe  case  of  diabetic  acidosis  in  an  H-year- 
old  girl  were  100  grams  of  water,  8  mM  of  chloride,  12  miVI  of  sodium 
and  6  niAl  of  potassium  per  kilogram  of  body  weight.  The  serum 
concentrations  of  phosphorus  decrease  somewhat  more  strikingly  dur- 
ing recovery  from  diabetic  acidosis  than  those  of  infants  with  diarrhea. 
The  changes  in  tissue  composition  in  diabetic  acidosis  apparently  re- 
semble those  of  infantile  diarrhea  except  for  the  hyperglycemia  and 
ketosis.  Recent  observations^'  indicate  that  the  elevation  of  blood  sugar 
expands  extracellular  fluids  and  dehydrates  the  cells  owing  to  its  osmotic 
effect.  Since  the  glucose  is  only  found  in  the  extracellular  fluids,  it  can 
exert  its  osmotic  effect  only  in  these  fluids.  A  blood  sugar  of  550  mgm. 
per  100  ml.  has  about  one  tenth  as  great  osmotic  pressure  as  that  of 
normal  plasma.  These  facts  must  be  taken  into  account  in  judging  the 
decrease  in  serum  electrolyte  concentrations  in  diabetic  acidosis. 

The  acidosis  of  renal  failure  has  not  been  studied  adequately  from 
the  point  of  view  of  changes  in  both  extracellular  and  intracellular 
composition.  Nephritic  patients  frequently  show  low  serum  concen- 
trations of  bicarbonate,  chloride  and  sodium,  but  the  intracellular 
changes  accompanying  these  changes  are  not  known.  The  usual  ex- 
planation of  the  serum  electrolyte  changes  is  failure  of  the  kidneys  to 
conserve  sodium  chloride  and  preserve  the  acid-base  balance  in  ad- 
vanced hyposthenuric  nephritis.  Certain  patients  with  chronic  nephritis 
have  shown  weakness  which  is  relieved  by  potassium  salts.  These 
patients  have  low  concentrations  of  potassium  in  serum^^  and  analyses 
of  other  nephritic  patients  with  acidosis  have  shown  low  potassium  in 
muscles'''.  The  logical  explanation  is  that  the  kidneys  are  unable  to 
conserve  potassium.  These  findings  suggest  that  deficit  of  potassium 
may  aggravate  acidosis  through  transfer  of  extracellular  sodium  to  the 
cells  in  patients  who  already  have  low  concentrations  of  sodium  and 
chloride  in  serum.  Thus  the  acidosis  of  nephritis  may  depend  on  deficits 
of  both  sodium  and  potassium  without  deficiency  in  water.  However, 
when  there  is  oliguria,  the  concentration  of  potassium  in  serum  may  rise 
to  levels  associated  with  disturbances  in  the  heart^*'  ^^'  ^^  Indeed,  potas- 
sium intoxication  is  one  of  the  events  leading  to  death  in  experimental 
anuria^^  and  in  some  cases  of  nephritis^^  The  intracellular  fluids  of  such 
patients  probably  are  high  in  potassium. 

All  the  disturbances  produced  by  loss  of  extracellular  water  and 

Vol.  I.  152 


96o    REGULATION  OF  BODY  WATER  AND  ELECl  ROLV  1 E 

electrolyte  may  result  from  the  immobilization  of  water  and  electro- 
lytes at  the  site  of  an  exudate  or  tissue  injury.  Burns  and  crushing 
injuries  to  muscles  are  examples  of  disturbances  of  this  type  which 
involve  no  loss  of  water  from  the  body*'^  It  has  been  shown  that  the 
fluids  that  accumulate  at  the  site  of  injury  contain  all  the  essential 
elements  of  extracellular  fluids  and  plasma.  Although  the  fluids  are  not 
lost  from  the  body  as  a  whole,  the  water  and  electrolytes  are  not  avail- 
able to  the  rest  of  the  tissues.  Thus,  it  is  not  surprising  that  traumatic 
shock  with  immobilization  of  extracellular  water  and  electrolytes  shows 
the  same  clinical  phenomena  of  peripheral  circulatory  collapse,  oliguria 
and  anoxia  of  the  tissues  as  are  encountered  in  medical  shock  produced 
by  losses  of  extracellular  electrolytes  and  water. 

When  the  circulation  is  interrupted  or  impaired  by  shock  or  ex- 
posure to  cold^"-  ",  the  intracellular  fluids  of  the  muscles  lose  potassium 
and  gain  sodium.  As  was  pointed  out  earlier,  transfer  of  extracellular 
sodium  to  the  cells  produces  metabolic  acidosis  when  there  is  failure  of 
renal  adjustment  of  body  electrolyte.  7  he  cellular  loss  of  potassium 
raises  the  concentration  of  potassium  in  serum.  If  renal  function  is 
adequate,  the  potassium  will  be  excreted  in  the  urine. 

A  similar  exchange  of  potassium  for  sodium  in  the  cells  takes  place 
in  anoxia  and  explains  the  rise  in  the  concentration  of  potassium  in  serum 
in  peripheral  vascular  collapse.  High  concentrations  of  potassium  in 
scrum  are  found  frequently  in  diarrheal  dehydration  and  diabetic  aci- 
dosis before  treatment  is  initiated  despite  the  fact  that  the  intracellular 
fluids  are  deficient  in  this  ion.  This  sort  of  reaction,  leading  to  urinary 
excretion  of  potassium,  explains  in  part  the  loss  of  this  ion  in  these  and 
other  similar  conditions.  However,  the  chief  interest  lies  in  the  fact 
that  internal  shifts  of  sodium  as  well  as  loss  of  sodium  from  the  body 
act  together  to  produce  acidosis. 

Alkalosis  usually  is  produced  by  primary  deficit  of  chloride  resulting 
from  vo'U/itiuir,  The  authors  have  determined  the  retentions  during 
recovery  in  4  cases  of  congenital  hypertrophic  stenosis.  In  all  there 
was  evidence  of  abnormally  Wmh  intracellular  sodium  before  treatment. 
Three  patients  retained  moderate  amounts  of  potassium  during  recov- 
ery, while  one  did  not.  Danowski  and  others^-  have  shown  by  balances 
that  more  potassium  is  retained  during  recovery  than  can  be  accounted 
for  by  the  retention  of  nitrogen.  Apparently  some  cases  of  alkalosis  due 
to  deficit  of  chloride  £Tet  enough  potassium  from  food  to  prevent  deficits 
of  this  ion,  but  others  develop  large  deficits  of  potassium  as  well  as  large 
losses  of  chloride  in  relation  to  sodium".   It  should  be  remembered  that 

Vol.  I.  152 


RELATION  OK  EXTRACELLULAR  TO  INTRA-  961 

CELLULAR  ELECl  ROLYTE 

the  presence  of  high  intracelkihir  sodium  in  alkalosis  indicates  that  the 
relative  excess  of  sodium  over  chloride  in  the  body  as  a  whole  is  much 
greater  than  that  which  is  revealed  by  analysis  of  the  serum  for  chloride 
and  sodium.  The  large  amount  of  intracellular  sodium  explains  the  slow 
response  of  some  cases  to  administration  of  sodium  chloride.  1  he  fact 
that  potassium  deficit  persists  means  that,  in  accordance  with  the  rela- 
tionships depicted  in  chart  ill,  the  kidneys  will  not  excrete  sodium  so  as 
to  increase  the  bicarbonate  in  the  scrum  until  cellular  potassium  is 
replaced. 

Prolono^ed  {rastric  suction  after  operations  provides  the  conditions 
for  the  development  of  alkalosis  with  potassium  deficiency.  The  re- 
moval of  gastric  fluid  depletes  the  body  of  more  chloride  than  sodium 
and  produces  alkalosis.  The  administration  of  sodium  chloride  facili- 
tates the  excretion  of  potassium  by  the  kidneys.  While  sodium  chloride 
usually  is  administered  in  sufficient  amounts  to  replace  extracellular 
electrolyte,  the  development  of  potassium  deficiency  alters  the  renal 
function  so  that  metabolic  alkalosis  persists.  Patients  subjected  to 
gastric  suction  are  likely  to  develop  low  concentrations  of  potassium 
in  serum.  Clinical  improvement  follows  replacement  of  potassium  as 
well  as  sodium  chloride^^  *''■  ^'''  *'. 

McQuarrie  and  others^'  first  called  attention  to  certain  cases  of 
Ciisb'm^'s  syiidro'iiie  which  have  alkalosis  refractory  to  administration 
of  sodium  chloride  and  ammonium  chloride  but  responding  to  potas- 
sium salts.  The  serums  show  not  only  high  concentrations  of  bicar- 
bonate but  low  chloride  and  potassium.  Kepler  and  others^''  "'  studied 
one  patient  who  recovered  from  alkalosis  after  removal  of  an  adreno- 
cortical tumor  but  again  developed  alkalosis  when  metastases  became 
manifest.  Analyses  of  the  muscle  of  these  cases  probably  would  show 
low  potassium  and  high  intracellular  sodium.  The  patients  sufi^er  from 
primary  deficit  of  potassium  produced  by  certain  adrenocortical  ster- 
oids which  increase  the  excretion  of  potassium  by  the  kidneys.  The 
same  picture  can  be  produced  by  repeated  injections  of  desoxycorti- 
costerone  acetate"  and  less  readily  by  diets  low  in  potassium.  The  experi- 
mental animals  receiving  desoxycorticosterone  show  high  intracellular 
sodium  and  low  muscle  potassium  together  with  marked  alkalosis  of 
the  serum-.  The  administration  of  cortisone  and  adrenocorticotropic 
hormone  involves  loss  of  potassium  and  alkalosis.  Part  of  the  efi^ect  of 
operations  in  producing  losses  of  potassium  may  be  increased  stimula- 
tion of  the  adrenal  cortex^'. 

Vol..  1.  152 


962     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

Edeina  represents  chiefly  expansion  of  the  extnicelkilar  water  and 
electrolyte.  The  mechanism  promoting  the  formation  of  edema,  which 
acts  locally  in  the  exchange  of  the  fluid  between  the  capillaries  and  the 
interstitial  fluids  are  as  follows:  increased  hydrostatic  pressure  in  the 
capillaries  in  heart  failure  and  venous  obstruction,  decrease  in  serum 
protein  concentration  in  nutritional  edema,  nephrosis,  nephritis  and 
liver  diseases,  the  presence  of  abnormal  amounts  of  proteins  in  inter- 
stitial fluids  in  allergic  reactions,  myxedema  and  acute  nephritis  and 
decreased  absorption  of  fluids  by  the  lymphatics  in  some  diseases.  Ulti- 
mately the  volume  and  concentration  of  body  fluids  are  controlled  by 
the  kidneys.  Disturbances  in  the  excretions  of  sodium  play  an  important 
role  in  the  genesis  of  edema  which  is  discussed  in  a  subsequent  part  of 
this  chapter. 

The  Expenditure  of  Water  and  Electrolyte 

The  intake  of  water  and  electrolyte  must  equal  the  losses.  For  this 
reason  knowledge  of  the  physiological  factors  controlling  expenditure 
enables  the  physician  to  plan  rationally  an  intake  that  meets  these  de- 
mands. The  important  pathways  of  expenditure  of  water  and  electro- 
lyte are  (i)  the  lungs  and  skin,  (2)  the  gastrointestinal  tract  and  (3) 
the  urine. 

Losses  jrovi  Lwigs  mid  Skin 

The  losses  from  the  lungs  and  skin  may  be  divided  into  the  insensible 
losses  occurring  when  there  is  no  sweat  and  those  involving  activity  of 
the  sweat  glands.  The  insensible  water  loss  excluding  sweat  is  roughly 
correlated  with  heat  production  so  that  42  grams  are  lost  for  each  100 
calories  produced'\  AVhen  there  is  no  sweat,  a  small  amount  of  electro- 
lyte is  also  lost  from  the  skin,  but  this  is  negligible  for  most  purposes. 


Stool  Water 

Stool  water  is  dependent  chiefly  on  the  residue  of  the  diet  which, 
in  general,  is  proportional  to  the  caloric  intake.  During  fasting  stool 
water  is  negligible  unless  there  is  diarrhea.  Normal  fecal  water  is  about 
4  grams  per  100  calories  of  the  diet  and  is  such  a  small  part  of  the  total 
water  expenditure  as  to  be  negligible  for  most  purposes. 

Vol.  I.  152 


EXPENDn  URE  OF  WATER  AND  ELECTROLYTE         963 

Kidney  Excretion 

The  volume  of  urine  must  be  sufficient  to  remove  the  excretory  load 
presented  to  the  kidneys.  The  substances  presented  for  excretion  are 
chiefly  the  end  products  of  protein  metabolism  together  with  other 
osmotically  active  substances  of  which  electrolytes  are  the  most  impor- 
tant. Renal  load  is  proportional  to  the  metabolic  mixture  being  burned 
or  the  intake.  Although  different  diets  contain  variable  amounts  of 
protein  and  electrolytes,  the  ordinary  diets  of  patients  are  sufficiently 
alike  to  permit  an  approximate  estimation  of  the  renal  load  from  caloric 
intake.  During  fasting  the  renal  load  consists  largely  of  the  end  prod- 
ucts of  protein  metabolism  together  with  electrolyte  freed  by  the  break- 
down of  tissues.  The  metabolic  mixture  during  fasting  probably  varies 
somewhat  with  age,  the  nutritional  state  and  the  length  of  fast.  When 
all  other  food  is  omitted,  administration  of  glucose  reduces  the  renal 
load  not  only  to  the  extent  that  protein  is  spared  but  also  by  abolishing 
ketosis  which  requires  excretion  of  these  acids  together  with  electro- 
lyte'- ^\  Minimal  protein  metabolism  is  attained  by  giving  4  to  5  grams 
of  carbohydrate  per  100  calories  metabolized,  hi  other  words  the  renal 
load  during  fasting  is  proportional  to  the  caloric  expenditure  except 
that  the  load  is  diminished  to  a  minimum  by  the  administration  of  glu- 
cose. The  concentration  of  the  urine  determines  the  volume  of  water 
required  to  contain  a  given  load.  The  volume  of  urine  is,  therefore, 
dependent  on  the  ability  of  the  kidneys  to  form  urine  of  varying  specific 
gravity,  on  the  renal  load  and  the  intake  of  water.  Knowledge  of  these 
relationships  enables  the  physician  to  estimate  the  volume  of  urine 
which  will  contain  the  substances  presented  to  the  kidneys  for  excre- 
tion and  to  plan  an  intake  that  will  meet  the  expenditure. 

Chart  V  shows  the  urinary  volume  per  100  calories  on  the  ordinate 
and  the  urinary  concentration  on  the  abscissa.  The  area  labeled  diet 
gives  the  urinary  volumes  for  the  usual  adult  diet.  The  area  marked 
glucose  gives  the  urinary  volumes  during  omission  of  all  food  except 
enough  glucose  to  produce  maximal  reduction  of  renal  load.  Complete 
fasting  requires  intermediate  volumes.  Artificially  fed  infants  fall  into 
the  lower  part  of  the  area  marked  diet.  Owing  to  the  low  content  of 
protein  and  electrolyte  in  human  milk,  the  renal  load  of  breast  fed 
infants  is  almost  as  low  as  that  indicated  by  the  glucose  area. 

Chart  V^  may  be  used  to  calculate  the  water  requirement  as  follows: 
(i)  the  area  appropriate  for  the  diet,  fasting  or  glucose  administration 
is  chosen;  (2)  from  the  chart,  the  urinary  volume  per  100  calories  is 

Vol.  I.  152 


964    REGULATION  OF  BODY  VVA  lER  AND  ELEC  I  ROLYTE 

obtained  for  an  appropriate  concentration,  usually  at  a  specific  gravity 
of  1.012;  (3)  the  caloric  production  is  estimated  from  the  age,  weight, 
activity  and  food  intake;  (4)  the  volume  of  urine  per  100  calories 
multiplied  by  one  hundredth  of  the  estimated  caloric  production  gives 
the  total  urinary  volume;   (5)    for  each    100  calories  metabolized  42 


WATER 

pzr 
100  cal. 

ml 


OSMOLS 
per  L 

SP.  6R. 


120 


100 


80 


60 


40 


20 


0.2 
.006 


0.4 

1.012 


0.6 

1.0)8 


0.8 
1.024 


1.0 
.030 


1.2 
.036 


CuARi'  V.  Urinar\'  water  per  loo  calories  of  food  or  loo  calories  of  hear  produc- 
tion as  related  to  uriiiar\'  concentration.  Tlic  area  marked  diet  gives  the  renal  load  per 
100  calories  of  the  usual  adult  diet,  w  hile  the  area  marked  gluct)se  gives  the  renal  load 
per  100  calories  of  heat  proiluction,  when  maximal  protein  sparing  is  produced  by  glu- 
cose administration  during  omission  of  all  other  food. 


grams  of  water  is  required  to  cover  the  insensible  water  losses.  The  sum 
of  the  total  urinary  volume  and  the  insensible  water  losses  gives  the 
water  expenditure  excluding  sweat,  stool  water  and  abnormal  losses. 
Since  complete  absence  of  perspiration  is  unlikely,  15  to  20  ml  per  loo 
calorics  metabolized  should  be  added  to  cover  total  water  expenditure 
in  the  absence  of  abnormal  losses  or  large  volumes  of  sweat. 
\'()i..  1.  152 


EXPENDITURE  OF  WATER  AND  ELECTROLYTE         965 

Forthc  normal  individual  without  sweat  on  a  normal  diet  and  having 
a  urinary  specific  gravity  of  1.012,  the  above  calculations  indicate  that 
water  expenditure  is  126  grams  per  100  calories  or  140  grams  assigning 
a  small  allowance  for  sweat  and  stool  water.  Since  babies  metabolize 
about  100  calories  per  kilogram  of  body  weight,  this  figure  gives  the 
water  requirement  of  infants  per  kilogram  of  body  w^eight.  An  adult, 
metabolizing  3,000  calories,  would  require  3,800  to  4,200  grams  or 
about  54  to  60  grams  per  kilogram  of  body  weight,  if  the  caloric 
expenditure  is  43  calories  per  kilogram.  If  the  values  are  calculated  for 
a  urinary  specific  gravity  of  1.024,  '^  baby  would  require  88  grams  per 
kilogram  of  body  weight,  if  there  is  no  sweating.  x\n  adult  would 
require  2,650  grams  or  38  grams  per  kilogram  of  body  \veight.  These 
figures  are  about  minimal  except  as  modified  by  reduced  caloric  pro- 
duction or  diets  giving  low  renal  loads.  It  should  be  noticed  that  calcu- 
lation of  the  water  expenditure  at  a  specific  gravity  of  1.012  provides 
sufficient  water  for  considerable  sweat,  if  the  kidneys  are  able  to  form 
a  concentrated  urine.  In  the  calculation  of  the  water  intake  it  should 
be  kept  in  mind  that  the  water  available  for  expenditure  is  equal  to  the 
preformed  water  intake  plus  the  water  of  oxidation.  1  he  latter  is  about 
12  grams  per  100  calories  metabolized  of  the  usual  metabolic  mixture. 
During  fasting  a  small  amount  of  water  is  made  available  for  expendi- 
ture by  decrease  in  tissue  water. 

71ie  usually  prescribed  intake  of  infants  is  150  grams  per  kilogram, 
which  would  lead  to  a  urinary  specific  gravity  of  1.008,  if  there  is  no 
sweat  or  abnormal  losses.  A  similar  intake  per  100  calories  metabolized 
in  an  adult  would  be  4,500  grams.  At  this  level  of  intake  the  kidneys 
could,  if  so  required,  provide  62  grams  of  water  per  100  calories  metab- 
olized for  sweat  or  abnormal  losses  or  a  total  of  1,860  for  the  average 
adult.  This  level  of  intake  apparently  is  appropriate  for  most  infants, 
since  they  cannot  readily  make  known  their  need  for  water.  It  may  be 
advisable  to  prescribe  as  high  an  intake  as  this  for  children  and  adults 
if  sweating  or  abnormal  losses  are  likely  to  occur.  Adults  will  volun- 
tarily regulate  their  intake  so  as  to  lead  to  moderately  concentrated 
urine. 

Unless  there  is  considerable  sweating  or  abnormal  losses,  the  intake 
of  electrolyte  with  the  diet  or  freed  from  breakdown  of  tissues  during 
fasting  is  sufficient  to  replace  the  losses  through  the  skin,  stools  and 
urine.  The  urine  can  be  rendered  practically  free  of  sodium  and 
chloride.  Data  on  the  ability  of  the  kidneys  to  conserve  potassium  are 
meac^er,  but  it  appears  that  the  normal  kidney  can  form  a  urine  which 

Vol.  I.  152 


966     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

contains  potassium  at  no  greater  concentration  than  that  of  serum. 
With  maximal  conservation  of  electrolyte  by  the  kidneys  the  urinary 
losses  are  about  0.2  niM  of  chloride  and  sodium  and  0.4  mM  of  potas- 
sium per  100  calories  metabolized.  The  minimal  daily  losses  in  a  year- 
old  infant  are  about  2  mM  of  sodium  chloride  and  4  mM  of  potassium. 
Corresponding  losses  for  an  adult  would  be  four-  to  sixfold. 

When  food  is  taken,  the  stool  losses  are  about  o.i  mM  of  sodium 
chloride  and  0.4  mM  of  potassium  per  100  calories  metabolized.  Stool 
electrolyte  is  negligible  during  fasting  unless  there  is  diarrhea. 

Aletabolic  studies  indicate  that  the  insensible  water  losses  are  slightly 
fi^reater  than  can  be  accounted  for  by  the  calorie  production  under 
ordinary  circumstances  in  infants''\  children"  and  adults''\  This  finding 
indicates  that  a  moderate  amount  of  sweat  usually  is  being  formed.  An 
average  estimate  is  10  grams  of  water  0.5  mM  of  sodium  and  chloride 
and  0.2  mA4  of  potassium  per  100  calories  metabolized.  The  average 
sweat  losses  in  adults  would  be  300  grams  of  water,  15  mM  of  sodium 
chloride  and  6  mM  of  potassium  per  day. 

Allowance  of  water  and  electrolyte  for  growth  is  of  little  practical 
significance  inasmuch  as  the  usual  diet  provides  abundant  water  and 
electrolyte.  The  daily  retentions  during  the  first  year  of  life  are  10 
grams  of  water,  0.6  mM  of  sodium,  0.4  mM  of  chloride  and  1.6  mM  of 
potassium.  During  periods  of  rapid  growth  the  retentions  may  be  twice 
these  values  and  from  the  third  to  tenth  year  about  half  as  great. 


Swiriimry 

In  summary,  the  water  requirements  can  be  predicted  fairly  confi- 
dently for  normal  conditions  by  the  calculations  described  in  the  dis- 
cussion of  chart  V.  The  minimal  losses  of  electrolyte  are  about  1.3  mM 
of  sodium,  potassium  and  chloride  per  100  calories  metabolized.  This 
indicates  that  the  minimal  requirements  in  the  first  year  are  about  0.5 
grams  of  sodium  chloride  and  0.3  i  grams  of  potassium  (0.6  grams  of 
potassium  chloride).  An  average  adult  would  require  1.5  grams  sodium 
chloride  and  2.9  grams  potassium  chloride.  Usually  somewhat  larger 
amounts  should  be  given,  since  minimal  expenditure  cannot  be  antici- 
pated. When  all  fluids  are  given  parenterally,  there  is  evidence  that 
losses  of  potassium  exceed  the  minimal  losses  by  a  considerable  amount. 
This  has  been  found  to  be  the  case  when  patients  are  given  all  fluids 
parenterally  after  operations.    The  amount  required  seems  to  be  2  to 

Vol..  L  152 


ABNORMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    967 

2.5  mM  per  100  calories  metabolized,  i.e.  about  50  niM  K  (3.7  grams 
potassium  chloride)  per  day  in  the  average  adult. 

Abnormal  Losses  of  Water  axd  Electrolyte 

Under  normal  conditions  without  sweating  about  two  thirds  of  the 
insensible  water  loss  occurs  by  diffusion  through  the  skin.  The  rate  of 
water  loss  from  the  respiratory  tract  depends  on  the  volume  of  respira- 
tory exchange  and  the  contents  of  water  in  the  inhaled  and  exhaled  air. 
These  are  in  turn  dependent  on  the  temperature  and  humidity  of  the 
environmental  air  since  the  exhaled  air  is  about  88  per  cent,  saturated 
at  body  temperature.  When  there  is  hyperpnea,  the  magnitude  of  the 
water  losses  through  the  lungs  is  difficult  to  measure  but  probably 
reaches  values  five  times  as  great  as  the  normal  rate'".  In  estimating  the 
importance  of  the  losses  of  water  from  the  lungs,  it  should  be  remem- 
bered that  an  increase  in  the  loss  by  the  lungs  may  be  partially  compen- 
sated by  decrease  in  the  activity  of  the  sweat  glands.  Water  loss  from 
the  lungs  is  not  accompanied  by  loss  of  electrolyte. 

The  insensible  loss  of  water  through  the  skin  is  dependent  chiefly 
on  the  gradient  for  diffusion  through  the  skin.  This  is  dependent  on 
the  skin  temperature  if  the  skin  is  dry.  A  small  amount  of  electrolyte 
is  lost  from  the  skin,  when  there  is  no  sweat,  presumably  through 
desquamation,  though  there  may  always  be  a  minimal  activity  of  the 
sweat  glands. 

Siveat 

The  factors  leading  to  the  production  of  sweat  are  discussed  in  the 
excellent  book  by  Adolph  and  associates'.  In  the  thermal  balance  of 
the  body  the  skin  acts  like  a  black  body  with  a  temperature  of  33.3 
degrees  centigrade  (92°  F.).  The  body  gains  heat  from  the  environ- 
ment and  objects  above  this  temperature  and  loses  heat  to  objects  and 
environment  below  this  temperature.  Under  conditions  leading  to 
minimal  water  losses  from  the  skin  about  one  fourth  of  the  heat  loss 
from  the  body  is  accounted  for  by  the  insensible  losses  of  water.  At  an 
environmental  temperature  of  about  26.7  degrees  centigrade  (80°  F.) 
body  temperature  is  maintained  without  sweating  and  without  greater 
production  of  heat  than  that  characteristic  of  rest.  At  a  given  tempera- 
ture the  radiant  energy  of  direct  sunshine  may  add  as  much  as  50  per 

Vol.  I.  152 


968     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

cent,  to  the  heat  balance  when  only  the  indirect  energy  from  the  sky 
is  acting  on  the  body.  Sweat  is  produced  normally  in  amounts  sufficient 
to  maintain  body  temperature  when  the  metabolic  production  of  heat 
and  the  positive  heat  balance  from  the  environment  are  greater  than  the 
losses  produced  by  evaporation  of  the  insensible  water  and  the  heat 
losses  through  radiation,  conduction  and  convection.  At  low  tempera- 
tures the  insensible  losses  cannot  be  decreased  so  the  heat  balance  is 
maintained  by  increased  heat  production  or  prevention  of  loss  by 
clothing.  The  efficiency  of  the  evaporation  of  sweat  is  not  seriously 
impaired  until  humidity  is  greater  than  80  per  cent.  Air  currents  accel- 
erate the  rate  of  evaporation  and  the  exchange  of  heat  with  the  environ- 
ment. 

The  volume  of  sweat  may  reach  2.4  liters  an  hour  in  man  at  hard 
work  at  a  high  environmental  temperature.  A  few  measurements  on 
normal  infants  kept  practically  nude  showed  that  raising  the  environ- 
mental temperature  from  26.7  to  33.3  centigrade  (80°  to  90°  F.) 
increased  the  loss  of  water  from  the  lungs  and  skin  from  48  to  108  grams 
per  kilogram  of  body  weight  per  day  '.  Presumably  at  least  as  much 
as  60  grams  of  sweat  per  kilogram  per  day  was  produced  at  the  higher 
temperature.  Adults  sitting  in  the  shade  at  similar  temperatures  showed 
comparable  sweating  per  unit  of  heat  production''.  The  calculated 
losses  of  sweat  in  infants  with  diarrhea  studied  at  comparable  tempera- 
tures in  August  in  Galveston  and  Dallas  averaged  70  grams  per  kilogram 
of  body  weight  per  day"\ 

When  the  environmental  temperature  is  higher  than  33.3  degrees 
centigrade  (92°  F.),  all  the  loss  of  heat  is  accounted  for  by  the  evapora- 
tion of  water.  Light  clothing  diminishes  the  amount  of  sweat  at  high 
temperatures  by  prevention  of  loss  of  drops  of  sweat  from  the  body 
surface  and  decrease  of  the  addition  of  heat  from  the  environment.  At 
lower  temperatures  clothing  sometimes  increases  the  volume  of  sweat 
by  decreasing  the  lieat  loss  by  radiation  and  convection.  iMere  observa- 
tion of  the  skin  is  inadequate  to  detect  the  onset  or  to  estimate  the 
amount  of  sweat.  For  a  lightly  clothed  individual  at  a  room  temperature 
of  28.8  to  ^2.1  {Hj;°  to  90°  F.)  an  allowance  for  tiic  loss  of  ^o  grams 
of  sweat  for  each  100  calories  metabolized  apparently^  is  indicated. 
Since  operating  rooms  arc  likely  to  be  quire  warm  and  the  patient  is 
kept  under  covers  and  lights  giving  off  a  good  deal  of  radiant  energy, 
water  loss  in  sweat  may  be  considerable  during  operations.  Air  condi- 
tioning of  operating  rooms  is  not  a  matter  of  comfort  for  the  surgeons 
but  may  be  a  requisite  for  low  operative  mortality.    Air  conditioning 

\^)i..  I.  152 


ABNORMAL  LOSSES  OF  WAIER  AND  ELECIROLN  1 1:    y6y 

and  avoidance  of  overhearing  are  important  therapeutic  measures  for 
patients  suffering  from  disturbances  in  the  metabolism  of  water  and 
electrolyte. 

The  quantity  of  electrolyte  in  sweat  has  been  found  to  be  so  variable 
that  any  prediction  of  the  composition  is  difficult  and  unreliable.  For 
clinical  purposes  the  concentration  of  sodium  and  chloride  may  be 
assumed  to  be  25  to  50  niAI  per  liter  and  that  of  potassium  15  niM. 
1  hese  values  may  be  somewhat  high  for  normal  acclimated  individuals. 
Actually,  analyses  of  sweat  indicate  that  the  concentration  of  sodium 
and  chloride  tend  to  be  at  about  equivalent  concentrations  and  to  vary 
from  5  to  100  mM  per  liter.  There  is  evidence  that  acclimatization  to 
hot  weather  is  accompanied  by  a  tendency  to  excrete  a  less  concentrated 
sweat'\  On  the  other  hand,  a  high  rate  of  sweating  usually  is  accom- 
panied by  increase  in  the  concentration  of  electrolyte.  Recent  work 
indicates  that  the  concentration  of  sodium,  potassium  and  chloride  is 
influenced  by  adrenocortical  hormones.  Conn  has  shown  that  patients 
with  adrenal  insufficiency  have  high  concentrations  of  sodium  and 
chloride  and  low  concentrations  of  potassium  in  the  sweat  produced 
in  response  to  heat.  In  contrast,  patients  with  adrenocortical  tumors  or 
ones  receiving  pituitary  adrenocorticotropic  hormone  or  desoxycorti- 
costerone  acetate  have  concentrations  of  sodium  and  chloride  that  are 
lower  than  normal,  while  those  of  potassium  are  higher  than  normaP^ 


Gastr(jiincstincil  Losses 

Abnormal  losses  of  water  and  electrolyte  from  the  e^astrointestinal 
tract  occur  as  a  result  of  vomiting,  diarrhea,  escape  of  fluids  throu[i^h 
intestinal  or  biliary  fistulae  or  by  aspiration  through  catheters  intro- 
duced into  the  stomach  or  upper  intestinal  tract.  The  approximate 
losses  can  be  estimated  from  the  volumes  and  the  composition  of  the 
fluids  lost.  Chart  Vl  sh()\\s  the  average  concentration  of  certain  (gastro- 
intestinal fluids.  Fhe  volumes  may  be  measured  but  usually  can  only 
be  estimated  approximately.  The  effect  of  the  losses  of  gastrointestinal 
fluids  is  discussed  ably  by  CJamblc,  particularly  as  they  affect  the  com- 
position of  extracellular  fluids"". 

As  the  chart  shows,  the  gastric  fluid  contains  more  chloride  than 
sodium  and  appreciable  amounts  Of  potassium.  As  excreted  by  the  chief 
cells,  the  chloride  concentration  is  somewhat  higher  than  that  of  sodium 
in  serum"'.  The  gastric  contents  are  the  result  of  mixing  the  acid  excre- 

VoL.  I.  152 


970    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

tion  of  the  chief  cells  with  the  neutral  or  slightly  alkaline  secretions  of 
other  cells.  The  amount  of  each  kind  of  secretion  is  so  variable  that 
gastric  contents  may  contain  considerably  more  chloride  than  sodium 
or  more  sodium  than  chloride.  The  loss  of  acid  gastric  juice  leaves  the 
body  with  relative  excess  of  sodium  available  to  form  bicarbonate  in 
extracellular  fluids.  This  type  of  alkalosis  is  characteristic  of  pyloric 
obstruction''^ 

CONCENTRATION  OF   GASTROINTESTINAL  FLUIDS 


1 

K 

Na 

H 

01 

HCO3 

K 

Na 

C  1 

HCO3 

K 

Na 

CI 

HCO3 

Bl  LE 
ACIDS 

K 

Na 

I 
0 


50 


00 


50 


m  M  per  L 


Chart  \'^I.  Concentrations  of  gastrointestinal  fluids.  From  above  downwards  the 
following  fluids  are  represented;  gastric,  external  pancreatic,  small  intestinal  and  hepatic 
bile. 


In  the  vomiting  of  renal  failure  and  as  a  result  of  certain  infections, 
the  fluid  is  not  acid  and  may  produce  no  change  in  acid-base  equilibrium 
or  even  acidosis.  In  certain  cases  of  vomiting,  typified  by  periodic 
vomiting  in  children,  acidosis  results  not  only  because  the  fluid  lost  is 
not  highly  acid  but  also  because  starvation  leads  to  non-diabetic  ketosis'^l 
I  ligh  intestinal  obstruction  and  loss  of  fluids  by  catheters  introduced 
into  the  upper  gastrointestinal  tract  after  operations  produce  alkalosis 

Vol.  I.  152 


ABNORMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    971 

because  the  losses  of  gastric  fluid  are  greater  than  the  losses  of  intestinal 
juices.  As  originally  "shown  by  Gamble,  there  are  appreciable  losses  of 
sodium  in  extracellular  fluids  even  w  hen  there  is  alkalosis.  Recent  work 
has  demonstrated  that  considerable  dcflcits  of  potassium  develop.  As 
discussed  in  the  flrst  section  of  this  chapter  this  loss  of  potassium  results 
lari^ely  from  changes  in  renal  excretion.  The  dcflcits  of  potassium 
follo\ving  post-operative  suction  may  be  so  large  as  t(v  produce  serious 
symptonis"  ^'  ^'''  '"■  '".  Although  gastric  juice  contains  moderate  amounts 
()f  potassium,  it  is  not  great  enough  to  account  for  the  potassium  deficits. 
Losses  of  hepatic  bile  and  the  external  secretion  of  the  pancreas 
produce  acidosis".  Drainage  from  flstulae  in  the  lower  part  of  the  small 
intestines  may  produce  acidosis  although  intestinal  juice  is  not  highly 
alkaline. 

Diarrheal  stools  vary  widely  in  composition.  In  some  patients  the 
electrolyte  concentrations  are' so  small  that  little  decrease  in  body 
electrolyte  develops  despite  the  loss  of  large  volumes  of  water  in  the 
stools.  In  other  patients  the  stools  contain  so  much  water  and  electro- 
lyte that  the  tissues  are  rapidly  depleted  of  both  water  and  electrolyte. 
The  concentrations  per  kilogram  of  stool  vary  from  12  to  90  ml\l  for 
sodium,  from  10  to  no  miM  for  chloride  and  from  10  to  80  niM  for 
potassium'^  The  daily  stool  losses  in  severe  infantile  diarrhea  are  about 
250  grams  of  water,  16  mM  of  sodium,  11  mM  of  chloride  and  8  niM 
oif  potassium.  In  adults  cholera,  severe  diarrhea  and  dysentery  probably 
lead  to  comparable  losses.  Sprue  and  celiac  disease  do  not  produce  as 
severe  losses  of  electrolyte  except  during  periods  of  exacerbation. 
Practically  all  types  of  diarrhea  tend  to  produce  greater  relative  losses 
of  sodiuni  and  potassium  than  chloride.  As  described  in  the  first  section, 
the  resulting  metabolic  acidosis  depends  on  shift  of  sodium  into  the  cells 
owiniT  to  deficit  of  potassium,  since  sodium  and  chloride  losses  tend  to 
be  in  equivalent  amounts. 

Gamble  and  associates''"'  and  Darrow"-  described  a  rare  type  of  con- 
frcnital  anomaly  of  intestinal  absorption  leading  to  obligatory  waterv 
stools  containincT  more  chloride  than  sodium.  The  patients  suffered 
from  continual  ^alkalosis  and  deficits  of  both  chloride  and  potassium. 
Recent  experimental  observations  indicate  that  rats  subjected  to  potas- 
sium deficiency  develop  diarrhea  in  which  the  stools  contain  more 
chloride  than  sodium'".  Albright  saw  a  similar  development  of  alkalosis 
in  a  patient  with  diarrhea  stools  containing  more  chloride  than  sodium''^ 
It  is  likely  that  potassium  deficit  under  certain  circumstances  alters 
intestinal  absorption. 
Vol.  L  152 


972     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

Renal  Losses 

A  discussion  of  the  role  of  renal  losses  in  disease  is  difficult,  because 
the  kidneys  play  the  chief  role  in  the  control  of  the  volume  and  con- 
centrations of  body  fluids.  However,  the  renal  regulation  is  merely  the 
crucial  activity  in  a  complex  process  integrated  by  the  regulation  of  the 
cardiovascular  system.  The  process  involves  the  activity  of  the  vegeta- 
tive nervous  system,  the  neurohypophysis,  the  humoral  and  neural 
control  of  the  blood  pressure  and  the  capillary  bed  and  both  parts  of 
the  adrenal  glands  and  other  endocrine  glands''*.  All  these  influences 
alter  renal  function  either  directly  or  indirectly  or  both. 

Vascular  Movements  of  Fluids 

The  movement  of  substances  within  the  body  and  the  exchange  of 
water,  gases  and  solids  with  the  outside  environment  is  accomplished 
by  the  rapidly  moving  fluids  of  the  vascular  compartments.  The  red 
cells  and  the  blood  plasma  are  about  one  fourth  of  the  total  extracellular 
constituents.  Although  the  red  cells  must  be  considered  intracellular 
from  the  point  of  view  of  their  composition,  their  function  is  intimately 
associated  with  that  of  blood  plasma.  Maintenance  of  adequate  volumes 
of  plasma  and  red  cells  is  essential  to  nomial  function  of  the  vascular 
system  and  the  kidneys.  On  the  other  hand,  disturbances  in  body  water 
and  electrolytes  are  reflected  by  changes  in  distribution  of  the  circu- 
lation and  the  concentrations  and  volumes  of  plasma.  As  noted  in  the 
first  section,  loss  of  extracellular  electrolyte  leads  to  decrease  in  plasma 
volume,  decrease  in  cardiac  output,  decrease  in  blood  pressure  and 
diminished  renal  function.  Increase  in  electrolyte  concentration  leads 
to  disturbances  in  cellular  activity  particularly  in  the  central  nervous 
system.  It  also  increases  the  rate  of  glomerular  filtration  and  the  flow  of 
blood  to  the  kidneys. 

If  the  r()le  of  the  kidney  in  controlling  the  volume  of  water  and  elec- 
trolyte in  the  body  is  neglected,  the  movement  of  fluids  between  the  vas- 
cular and  interstitial  fluids  is  governed  by  a  balanced  exchange^"'  ^\  The 
movement  of  water  and  diflfusable  ions  and  molecules  out  of  the  capil- 
laries is  favored  by  the  hydrostatic  pressure  within  the  capillaries  and 
the  colloid  osmotic  pressure  of  the  perivascular  fluids;  the  movement 
of  these  substances  into  the  capillaries  is  favored  by  the  colloid  osmotic 
pressure  of  the  plasma  and  the  hydrostatic  pressure  of  the  perivascular 

Vol.  I.  1 52 


ABNORiMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    973 

fluids  which  is  niaint.iined  by  the  tissue  tension.  An  example  of  this 
balanced  mechanism  is  seen  in  the  portal  circulation  where  low  capillary 
pressure  is  balanced  by  high  colloid  pressure  in  the  perivascular  fluids 
brought  about  by  increased  permeability  of  the  liver  capillaries  to  pro- 
tein. Local  alterations  in  the  exchange  of  fluid  may  be  brought  about 
by  changes  in  the  capillary  bed.  The  lymph  channels  provide  an  alter- 
nate route  for  the  return  of  vascular  fluid  getting  into  the  interstitial 
spaces.  The  lymph  seems  to  be  concerned  particularly  with  the  return 
of  proteins  from  interstitial  fluids.  The  non-renal  factors  controlling 
the  distribution  of  body  fluids  explain  most  local  accumulations  of  fluid. 
While  theoretically  the  same  factors  can  explain  generalized  edema, 
recent  studies  show  that  renal  as  well  as  non-renal  factors  are  involved 
in  the  genesis  of  generalized  edema. 

Kidneys  in  Relation  to  Body  Fluids 

Normally  the  volume  of  fluid  in  the  vascular  compartment  is  ad- 
justed to  the  function  of  maintaining  the  exchange  of  metabolites  in 
vital  organs  first  by  redistribution  of  the  circulation  according  to  the 
need  but  ultimately  by  altering  the  volume  of  plasma  and  extracellular 
fluid'\  Present  knowledge  of  renal  physiology  is  inadequate  to  explain 
how  the  kidneys  maintain  the  volume  and  concentrations  of  body  fluid. 
However,  it  should  be  useful  to  point  out  certain  mechanisms  that 
probably  are  involved. 

According  to  one  theory"'-  the  distal  tubules  reabsorb  sodium  in 
quantities  which  are  relatively  constant  under  some  circumstances.  If 
this  be  true,  the  excretion  of  sodium  could  be  regulated  in  part  by 
changes  in  the  rate  of  glomerular  filtration  and  changes  in  the  rate  of 
reabsorption  of  water  and  sodium  in  the  distal  tubules.  Since  the  reab- 
sorption  of  water  and  salt  in  the  proximal  tubules  is  proportional  to  the 
rate  of  filtration,  the  sodium  and  water  delivered  to  the  distal  tubules 
varies  directly  with  the  rate  of  glomerular  filtration.  If  the  amount  of 
water  and  salt,  which  reaches  the  distal  tubules,  is  greater  than  the  rate 
of  distal  absorption,  sodium  is  excreted,  while  if  the  amount  is  less  than 
the  rate  of  distal  absorption,  practically  all  the  sodium  will  be  returned 
to  the  body.  Since  higher  concentrations  of  sodium  in  serum  lead  to 
increased  glomerular  filtration,  a  mechanism  thereby  is  provided  for 
regulating  the  volume  as  well  as  the  concentrations  of  extracellular 
fluids.  The  weakness  of  the  theory  lies  in  the  fact  that  variations 
in  sodium   excretion   have   been   found   to   occur  without   change   in 

Vol.  1.  152 


974    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

glomerular  filtration,  perhaps  in  part  because  the  methods  of  measure- 
ment introduce  alterations  in  this  rate.  It  is  likely,  ho\\'ever,  that  some 
such  mechanism  is  involved  and  explains  the  regulation  of  the  volume 
and  concentrations  of  extracellular  fluids  as  well  as  the  disturbances  in 
this  regulation. 

The  iieiirohypophysis  is  integrated  into  this  system  since  the  pro- 
duction of  antidiuretic  hormone  increases  when  serum  electrolyte  con- 
centration rises  and  decreases  when  serum  electrolyte  concentration 
diminishes.  The  following  factors  have  been  noted  to  be  accompanied 
by  changes  in  the  rate  of  sodium  excretion:  fluctuations  in  the  rate 
of  glomerular  filtration,  changes  in  the  venous  pressure,  changes  in 
the  renal  blood  flow,  alterations  in  the  activity  of  the  adrenal  glands  and 
the  hypophysis  and  hypoproteinemic  states.  The  exact  mechanism  by 
which  the  body  achieves  regulation  of  the  volume  as  well  as  the  con- 
centrations of  body  fluids  apparently  involves  some  combination  of 
these  factors  controlling  the  circulation,  the  neurohypophysis  and  the 
kidneys. 

Renal  excretion  may  be  divided  into  three  phases,  the  first  of  which 
is  the  formation  of  a  filtrate.  With  normal  glomeruli  the  amount  of 
filtrate  is  influenced  chiefly  by  the  pressure  in  the  glomerular  capillaries 
which  in  turn  is  controlled  by  the  local  and  general  factors  regulating 
the  circulation.  Glomerular  filtration  may  be  diminished  by  constric- 
tion of  the  renal  arterioles  which  decreases  the  circulation  to  the 
kidneys.  This  type  of  reaction  occurs  in  dehydration  and  shock.  At  a 
given  extracellular  volume,  the  glomerular  filtration  is  increased  by 
elevation  of  the  concentration  of  sodium  in  serum.  Glomerular  filtra- 
tion may  be  diminished  by  decrease  in  the  number  of  glomeruli  or  by 
diseases  of  the  glomeruli. 

Second,  about  85  per  cent,  of  the  water  and  electrolyte  which  is 
filtered  through  the  glomeruli  is  reabsorbed  by  the  proximal  tubules". 
The  proportion  of  this  reabsorption  may  vary  between  60  to  90  per 
cent,  of  the  filtered  water  and  electrolyte.  Since  this  operation  is  pro- 
portional to  the  rate  of  filtration,  most  of  the  reabsorption  of  water, 
sodium,  chloride  and  bicarbonate  is  accomphshed  by  a  process  which 
returns  a  large  part  of  the  filtered  water  and  electrolyte  to  the  blood. 
The  evidence  indicates  that  relatively  more  bicarbonate  than  chloride 
is  reabsorbed  at  this  stage  of  urine  formation.  Normally  practically  all 
the  glucose  is  reabsorbed,  and  most  of  the  urea  remains  in  the  urine  of 
the  proximal  tubules.  The  osmotic  pressure  remains  the  same  as  that 
Vol.  I.  152 


ABNORMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    975 

of  the  plasma  since  the  proximal  rul)ulcs  arc  freely  permeable  to  water. 
The  loop  of  Llenle  seems  especially  adapted  to  equalizing  the  osmotic 
pressure.  The  reabsorption  of  water  is  dependent  on  tiie  active  trans- 
port of  sodium  and  bicarbonate  by  the  proximal  tubules.  If  glucose  is 
not  completely  reabsorbed,  or  if  large  amounts  of  other  osmotically 
active  substances  remain,  less  water  and  electrolyte  are  reabsorbed  and 
more  are  delivered  to  the  distal  tubules. 

Third,  urine  is  formed  from  the  isosmotic  fluid  of  the  proximal 
tubules  by  the  distal  tubular  cells  which  reabsorb  water  and  sodium  and 
reabsorb  or  excrete  other  electrolytes  and  other  substances.  The  various 
operations  are  rather  specific,  and  at  least  the  absorption  of  water  and 
sodium  can  be  carried  out  more  or  less  independently  of  each  other. 
Thus,  the  volume  of  water  reabsorbed  is  influenced  by  the  antidiuretic 
hormone  of  the  hypophysis.  In  the  absence  of  the  antidiuretic  hormone 
large  volumes  of  urine  of  low  specific  gravity  are  excreted,  while  under 
the  influence  of  this  hormone  the  urine  can  be  maximally  concentrated 
by  the  normal  kidney.  By  an  essentially  separate  process  sodium  may 
be  reabsorbed  almost  completely,  or  a  large  part  of  the  sodium  reaching 
the  distal  tubules  may  be  excreted.  The  rate  of  sodium  reabsorption  is 
normally  regulated  so  as  to  maintain  the  volume  and  concentration  of 
body  fluids.  In  this  process  the  antidiuretic  hormone  plays  an  important 
role' '.  While  the  necessary  modifications  of  the  rate  of  reabsorption  of 
sodium  may  be  mediated  ultimately  by  adrenocortical  hormones,  so- 
dium reabsorption  is  increased  by  low  concentration  of  sodium  in 
plasma,  Iom-  filtration  rates  and  high  venous  pressures.  It  is  also  modified 
by  processes  regulating  urinary  acidity.  The  adrenocortical  hormones 
and  to  a  less  extent  other  related  steroids  diminish  the  excretion  of 
sodium'^  ' '.  If  the  venous  pressure  is  raised  in  one  kidney,  the  tubular 
reabsorption  of  sodium  is  increased  in  this  kidney  but  not  in  the  other 
one  with  unaltered  circulation.  Since  the  rate  of  glomerular  filtration 
remains  the  same  in  both  kidneys,  tubular  reabsorption  may  be  altered 
by  the  high  venous  pressure  without  hormonal  influences  or  changes  in 
the  rate  of  glomerular  filtration'". 

The  regulation  of  the  acidity  of  the  urine  provides  the  mechanism 
for  excreting  unusual  loads  of  acids  or  alkalis''  '\  In  this  operation, 
hydrogen  ions  are  exchanged  for  other  cations  by  a  process  that  is 
intimately  connected  with  the  rate  of  reabsorption  of  bicarbonate  and 
carbonate'"  "".  When  the  serum  bicarbonate  is  below  the  nomial  level, 
an  acid  urine  is  excreted  which  contains  practically  no  bicarbonate. 
When  the  plasma  bicarbonate  is  above  28  niEq  per  liter,  about  28  mKc] 

Vol.  1.  152 


976    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

of  bicarbonate  are  reabsorbed  for  each  liter  of  glomerular  filtrate. 
While  a  large  part  of  the  bicarbonate  reabsorption  is  accomplished  by 
the  proximal  tubules,  the  final  regulation  is  carried  out  by  the  distal 
tubules.  Thus  sodium  and  potassium  are  saved  in  acidosis,  and  chloride 
is  saved  in  alkalosis.  The  reabsorption  of  chloride  is  reciprocally  related 
to  bicarbonate  reabsorption,  and  the  sum  of  the  two  returned  to  the 
body  is  approximately  constant  for  a  given  amount  of  glomerular 
filtrate.  Since  the  reabsorption  of  cations,  chiefly  sodium,  is  related  to 
the  sum  of  chloride  and  bicarbonate  taken  back  into  the  body,  the 
electrolyte  pattern  of  the  plasma  is  determined  by  these  processes. 
Ammonia  isi  excreted  promptly  in  the  urine  in  response  to  an  acid  load, 
but  only  after  one  to  several  days  are  large  amounts  of  acids  excreted 
by  this  mechanism.  During  recovery  from  acidosis  there  is  a  delay  in 
the  decrease  in  ammonia  formation  so  that  there  is  a  tendency  for  body 
sodium  to  become  higher  than  normal  during  recovery  from  acidosis. 
With  the  introduction  of  large  loads  of  acid  to  be  excreted,  sodium  is 
at  first  lost  from  the  body.  Later,  excretion  of  potassium  diminishes  the 
losses  of  sodium  but  may  produce  deficits  of  potassium.  Finally,  am- 
monia excretion  may  achieve  a  satisfactory  conservation  of  fixed 
cations**^ 

The  formation  of  an  alkaline  urine  enables  the  kidneys  to  excrete 
large  amounts  of  bicarbonate  and  the  equivalent  amounts  of  cations. 
At  high  levels  of  bicarbonate,  the  urinary  pressure  of  carbon  dioxide 
rises.  It  is  noteworthy  that  depletion  of  sodium  and  potassium  as  well 
as  chloride  leading  to  alkalosis  is  accompanied  by  excretion  of  an  acid 
urine.  Thus,  the  formation  of  an  alkaline  urine  is  not  a  simple  response 
to  an  alkaline  plasma  but  is  modified  by  deficits  of  water  and  electrolyte. 

The  regulation  of  body  potassium  by  renal  excretion  only  recently 
has  received  the  attention  that  it  deserves.  Potassium  can  be  excreted 
by  the  renal  tubules  since  the  urine  may  contain  more  potassium  than 
can  be  accounted  for  by  the  glomerular  filtrate^-.  The  tubules  are 
capable  also  of  reabsorbing  potassium  against  a  concentration  gradient 
since  the  urinary  concentration  may  be  less  than  tliat  of  the  plasma.  It  is 
probable  that  potassium  is  almost  entirely  reabsorbed  in  the  proximal 
tubules  or  at  least  reabsorbed  to  the  same  extent  as  the  sodium.  In  this 
case  the  usual  process  is  excretion  by  the  distal  tubules. 

Urinary  potassium  rises  rapidly  in  response  to  increase  in  plasma 
potassium  concentration.  Adults  can  excrete  as  much  as  five  times  the 
usual  daily  load  of  4  grams.  When  potassium  intake  is  low,  urinary 
excretion  is  diminished,  but  some  potassium  is  found  always  in  the  urine. 

Vol.  I.  152 


ABNORMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    977 

The  kidneys  seem  to  have  httle  difficulty  in  rendering  the  urinary  con- 
centration at  least  as  low  as  that  of  the  plasma.  Nomially  the  rate  of 
potassium  excretion  maintains  the  plasma  concentration  within  narrow 
limits. 

Cellular  potassium  is  maintained  by  equilibrium  with  the  plasma 
potassium.  Under  certain  circumstances  potassium  is  released  from  the 
cells  to  extracellular  fluids  and  excreted.  Often  it  is  difficult  to  decide 
whether  the  loss  is  dependent  primarily  on  the  release  from  the  cells  or 
increased  excretion  by  the  kidneys  leading  secondarily  to  cellular  loss. 
A  disturbance  within  the  cells,  w^hich  releases  potassium,  probably  is 
in  part  the  explanation  of  potassium  losses  in  alkalosis  and  in  response 
to  desoxycorticosterone  acetate  and  adrenocortical  hormones.  Disturb- 
ances in  carbohydrate  metabolism  in  diabetic  acidosis  and  other  changes 
in  cellular  metabolism  in  anoxia,  shock,  dehydration  and  acidosis  pro- 
duce a  similar  release  of  potassium  from  the  cells.  Urinary  potassium 
rises  so  quickly  in  response  to  increase  in  plasma  bicarbonate  that  the 
initial  effect  probably  is  chiefly  renal.  However,  urinary  potassium 
may  become  quite  low  in  chronic  alkalosis  after  considerable  depletion 
of  intracellular  potassium.  As  was  indicated  previously,  excretion  of 
large  loads  of  acid  lead  to  urinary  losses  of  potassium.  In  part  this  seems 
to  depend  on  factors  involved  in  the  excretion  of  large  loads  of  acids. 
However,  acidosis  probably  also  releases  potassium"  from  the  cells. 
Indeed,  Elkinton  and  Winkler''^  produced  evidence  that  potassium  is 
released  from  the  cells  with  loss  of  body  water. 

The  mechanism  involved  in  the  formation  of  an  acid  or  alkaline 
urine  is  chiefly  responsible  for  the  preservation  of  the  acid-base  bal- 
ance of  the  blood  and  the  body  content  of  electrolyte.  In  alkalosis  urine 
chloride  usually  decreases  owing  to  increase  in  urinary  bicarbonate. 
However,  it  is  noteworthy  that  acid  urine  is  excreted  in  alkalosis  that 
is  accompanied  by  marked  deficit  of  body  electrolyte'^  The  role  of 
the  relative  deficits  of  sodium  and  potassium  to  this  phenomenon  has 
not  been  investigated.  Potassium  deficit  leads  to  increased  reabsorption 
of  bicarbonate  and  increased  excretion  of  chloride  since  potassium 
deficit  tends  to  produce  chloride  deficit.  Similarly,  alkalosis  due  to 
chloride  deficit  leads  to  increased  potassium  excretion  since  alkalosis 
tends  to  produce  deficiency  of  potassium.  Thus  not  only  does  the 
kidney  control  body  composition,  but  renal  function  is  determined  by 
body  composition. 

The  abnormalities  in  urine  formation  involve  so  many  factors  that 
the  alterations  in  renal  function  of  each  case  may  have  to  be  analysed 

Vol.  I.  152 


978     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

individually.  However,  it  is  possible  to  classify  the  various  defects  of 
urinary  excretion  into  the  following  types:  (i)  obligatory  water  ex- 
cretion with  little  loss  of  electrolyte,  (2)  obligatory  sodium  excretion, 
accompanied  by  proportionally  smaller  losses  of  water  and  (3)  exces- 
sive renal  reabsorption  of  sodium  and  Mater.  In  each  type  disturbances 
in  the  regulation  of  the  acid-base  equilibrium  may  develop,  and  this 
factor  must  be  evaluated  separately. 

It  is  obvious  that,  if  the  kidneys  excrete  water  at  a  greater  rate  than 
it  is  taken  into  the  body,  the  serum  electrolyte  concentrations  will  rise 
unless  electrolyte  is  excreted  also.  The  body  will  contain  low  amounts 
of  water,  and  the  senmi  will  show  an  increase  in  concentration  of  elec- 
trolyte. The  state  of  body  water  and  electrolyte  is  hypertonic  dehydra- 
tion. Obligatory  polyuria  leading  to  losses  of  water  and  but  little 
change  in  body  sodium  and  chloride  has  been  described  in  infants  as  a 
result  of  an  anomaly  of  renal  function**"'  '■'^'  **'.  The  patients  are  all  males, 
they  fail  to  grow,  have  fever  unexplained  by  infections  and  are  mentally 
deficient.  The  diuresis  fails  to  respond  to  the  antidiuretic  homione. 
Often  the  loss  of  water  becomes  so  rapid  that  the  patients  spend  prac- 
tically all  their  time  drinking.  The  serums  show  very  high  concentra- 
tions of  sodium  and  chloride  without  striking  acidosis.  The  continued 
reabsorption  of  sodium  and  chloride  in  the  face  of  rising  serum  concen- 
tration is  the  essential  feature  of  the  disease.  The  changes  in  cellular 
composition  are  not  known.  These  patients  require  low  intakes  of 
sodium  chloride  as  well  as  high  intakes  of  water. 

Diabetes  insipidus  results  from  deficient  production  of  antidiuretic 
hormone  owing  to  injury  of  the  neurohyphophysis^^l  The  patients  usu- 
ally do  not  suffer  from  dehydration,  since  they  develop  thirst,  which  is 
gratified  by  drinking  large  amounts  of  water.  Since  the  distal  tubules 
seem  to  function  normally  with  respect  to  reabsorption  of  sodium  and 
other  electrolytes,  there  are  usually  no  disturbances  in  acid-base  equi- 
librium or  plasma  electrolyte  concentration.  If  the  intake  of  sodium 
chloride  is  high,  salt  is  excreted  in  large  volumes  of  dilute  urine.  If  the 
intake  of  sodium  chloride  is  low,  the  kidneys  save  sodium  chloride  and 
excrete  somewhat  smaller  amounts  of  dilute  urine.  The  patients  seem 
to  suffer  chiefly  from  difficulty  in  drinking  enough  water  to  avoid  thirst 
produced  by  the  obligatory  urinary  water  losses.  The  symptoms  of 
thirst  and  the  polyuria  can  be  overcome  temporarily  by  injections  of 
antidiuretic  hormone  or  by  spraying  the  hormone  on  the  nasal  mucous 
membranes'*''.  * 

Adrenal  insufficiency  is  perhaps  the  purest  type  of  obligatory  cxcrc- 
Vol.  I.  152 


ABNORMAL  LOSSES  OF  WATER  AND  ELECH  ROLVTE    979 

rion  of  sodium"".  Although  the  urinary  excretion  of  sodium  and  chloride 
is  accompanied  by  decrease  in  body  water,  the  concentrations  of  sodium 
and  chloride  in  serum  are  low,  and  moderate  acidosis  develops.  This 
indicates  that  the  losses  of  sodium  and  chloride  are  relatively  greater 
than  those  of  water.  The  patients  suffer  from  hypotonic  dehydration. 
The  volume  of  extracellular  fluids  is  decreased  while  the  cells  have  high 
water  contents.  Although  the  primary  defect  in  renal  function  is  failure 
to  conserve  sodium,  the  final  picture  is  the  result  of  circulatory  and 
renal  failure  produced  by  deficit  of  extracellular  electrolytes.  Sodium 
deficiency  is  the  chief  explanation  of  the  diminished  circulation,  the 
low  blood  pressure,  the  low  blood  volume,  the  decrease  in  the  rate  of 
glomerular  filtration,  the  rise  in  non-protein  nitrogen  and  the  failure 
to  regulate  the  urinary  acidity.  These  disturbances  are  corrected  for 
the  most  part  as  long  as  body  electrolytes  are  kept  normal  by  the  ad- 
ministration of  suitable  amounts  of  sodium  chloride  or  a  mixture  of 
sodium  chloride  and  sodium  bicarbonate'^  '"'.  Administration  of  desoxy- 
corticosterone  acetate  or  cortical  extract  corrects  the  absorption  of 
sodium  by  the  renal  tubules,  and  with  the  restoration  of  body  electro- 
lyte renal  function  becomes  essentially  normal. 

There  is  evidence  that  potassium  tends  to  be  retained  in  adrenal 
insufficiency,  especially  when  the  loss  of  extracellular  electrolytes  leads 
to  circulatory  changes  and  diminished  glomerular  filtratioir'"  "'  '-.  The 
muscles  under  these  circumstances  may  contain  excessive  amounts  of 
potassium.  Some  evidence  has  been  assembled  that  cortical  hormones 
increase  cellular  water''.  If  this  is  true,  the  increase  in  intracellular 
water  accompanying  loss  of  extracellular  electrolytes  may  not  be  as 
great  as  would  be  produced  by  a  similar  loss  in  animals  with  intact 
adrenals. 

Adrenal  hormones  are  necessary  for  the  diuresis  of  water  since  intact 
adrenals  or  cortical  hormones  are  necessary  for  the  development  of  the 
picture  of  diabetes  insipidus"'.  This  observation  is  the  basis  of  the  test 
for  adrenal  insufficiency  showing  failure  of  diuresis  in  response  to  a 
water  load''\ 

A  large  part  of  the  picture  of  Addisonian  crisis  is  explained  by  defi- 
cits of  extracellular  electrolytes.  Adequate  supplies  of  sodium  chloride 
enable  the  patients  to  survive  and  perform  the  usual  metabolic  functions, 
though  the  response  to  stress  is  slow  and  inadequate.  However,  it  is 
clear  that  adrenal  insufficiency  involves  more  than  disturbances  due  to 
loss  of  body  water  and  electrolytes".  Glyconeogenesis  from  protein 
and  other  responses  to  cortical  hormones  are  not  clearly  associated  with 
Vol.  L  152 


98o    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

the  electrolyte  disturbances.  Nevertheless,  Addisonian  patients  have 
striking  adverse  reactions  to  relatively  small  amounts  of  potassium  in 
food,  especially  when  there  are  deficits  of  sodium  and  chloride.  This 
response  has  never  been  satisfactorily  explained.  Kendall  has  postulated 
that  the  adrenal  cortex  enables  the  body  to  be  freed  from  the  vicissitudes 
of  electrolyte  metabolism"'. 

Although  desoxycorticosterone  acetate  restores  renal  function  with 
respect  to  reabsorption  of  water  and  sodium,  the  compound  may  lead 
to  excessive  excretion  of  potassium.  Cardiac  injury  may  result  particu- 
larly if  the  intake  of  sodium  chloride  is  high  and  that  of  potassium  low"''. 
Diets  should  not  be  low  in  potassium  or  high  in  sodium  chloride  when 
desoxycorticosterone  is  administered.  However,  Addisonian  patients 
do  better  with  diets  low  in  potassium  and  high  in  sodium  chloride  when 
no  hormonal  therapy  is  given^". 

The  excessive  excretion  of  sodium  in  hyposthenuric  renal  insuffi- 
ciency usually  is  accompanied  by  other  defects  in  renal  function.  While 
the  generalized  effects  of  deficit  of  extracellular  water  and  electrolytes 
may  develop  and  aggravate  the  disturbances  in  the  kidneys,  this  does 
not  usually  take  place.  The  kidneys  may  continue  to  excrete  sodium 
and  chloride  while  the  serum  concentrations  of  these  ions  remain  low 
and  body  water  is  relatively  normal.  The  body  seems  to  become  ad- 
justed to  low  concentrations  of  electrolytes.  The  urine  cannot  be  ren- 
dered highly  acid,  ammonia  is  not  adequately  formed  in  response  to 
acidosis,  phosphate  and  sulphate  are  poorly  excreted,  and  the  urinary 
concentrations  remain  constant  and  low.  Since  the  usual  diet  requires 
the  excretion  of  an  acid  urine  in  order  to  preserve  body  electrolytes, 
acidosis  results.  Some  cases  of  chronic  renal  insufficiency  have  shown 
flaccid  paralysis  accompanied  by  low  serum  concentrations  of  potas- 
sium and  responding  to  administration  of  potassium^-.  The  kidneys  of 
these  patients  apparently  are  unable  to  conserve  potassium.  It  is  likely 
that  diets  high  in  sodium  chloride  aggravate  this  tendency.  Some  pa- 
tients with  chronic  nephritis  develop  acidosis  associated  with  deficits 
of  both  sodium  and  potassium.  The  decrease  in  extracellular  sodium  is 
explained,  in  part,  by  the  transfer  of  sodium  to  the  cells  owing  to  deficit 
of  potassium,  since  analyses  of  the  muscles  have  shown  low  potassium  and 
high  intracellular  sodium^^ 

In  the  terminal  stages  of  nephritis,  particularly  when  oliguria  has 

developed,  the  excretion  of  potassium  is  diminished,  serum  potassium 

concentration   rises,   and   death   may   result   from    potassium   intoxica- 

tion^^'  *'.    Along  with   the   elevation   of  serum   potassium,   a   few   pa- 

VoL.  I.  152 


ABNORiMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    981 

rients  have  shown  a  flaccid  paralysis  and  weakness  with  electrocardio- 
graphic changes  characteristic  of  high  serum  potassium  and  relief  of  the 
symptoms  when  the  administration  of  saline  solutions  has  reduced  the 
serum  potassium  concentration'*'. 

If  the  patients  have  circulatory  disturbances  as  the  results  of  decrease 
in  the  volume  or  concentrations  of  extracellular  fluids,  improvement 
follows  administration  of  water  and  sodium  chloride.  Renal  function 
also  may  be  improved  in  some  cases  with  low  serum  electrolyte,  if  suffi- 
cient sodium  chloride  and  sodium  bicarbonate  are  administered  to 
replace  the  urinary  losses  despite  little  effect  on  the  circulation.  This 
effect  seems  to  depend  on  increase  in  the  urine  volume.  It  is  difficult  to 
achieve  stable  normal  concentrations  of  electrolyte  in  the  serum  of 
many  cases  of  nephritis.  If  excessive  amounts  of  salt  are  given,  serum 
electrolyte  concentrations  may  become  abnormally  high,  or  edema  may 
be  produced  or  aggravated.  Relief  from  acidosis  follows  the  adminis- 
tration of  sodium  bicarbonate,  but  the  effect  seldom  is  prolonged.  If 
large  amounts  of  sodium  bicarbonate  are  given  to  patients  with  chronic 
nephritis,  a  highly  alkaline  urine  is  not  formed,  and  alkalosis  is  produced. 

There  is  evidence  that  administration  of  large  amounts  of  sodium 
bicarbonate  in  the  therapy  of  peptic  ulcer  produces  renal  insufficiency 
as  well  as  profound  alkalosis"'"  ■ -.  The  patients  lose  their  appetites  and 
develop  lassitude,  weakness,  headache,  nausea  and  vomiting.  Mild 
stupor,  coma  or  psychic  disturbances  occur.  The  non-protein  nitrogen 
rises  and  returns  to  nonnal  slowly  only  after  the  serum  electrolyte 
concentrations  are  restored.  In  some  cases  the  alkalosis  seems  to  have 
produced  permanent  renal  damage.  It  is  not  certain,  however,  that 
alkalosis  permanently  injures  the  normal  kidney,  but  there  is  little  doubt 
that  it  aggravates  the  pathological  process  in  the  kidney  already  ab- 
normal   . 

Disturbances  leading  to  excessive  reabsorption  of  water  and  electro- 
lytes tend  to  produce  edema.  As  was  previously  indicated,  the  function 
of  the  distal  tubules,  which  provide  the  mechanism  for  the  reabsorption 
of  water  and  electrolyte,  is  the  one  that  is  ultimately  responsible  for 
regulating  the  volume  and  concentrations  of  body  fluids.  Particularly 
in  this  operation  the  kidneys  are  under  the  influence  of  the  factors  con- 
trolling the  circulation,  the  neurohypophvsis  and  the  endocrines.  It  is 
not  surprising,  therefore,  that  disturbances  in  the  reabsorption  of  water 
and  electrolyte  by  the  kidney  may  arise  primarily  from  generalized 
circulatory  diseases  and,  even  when  the  kidneys  are  primarily  involved, 
disturbances  involving  control  of  the  circulation  develop.  The  circula- 
VoL.  I.  152 


y82     REGULATION  OF  BODY  WATER  AND  ELECEROLYTE 

tory  disturbances  aggravate  the  difficulty  of  renal  origin,  and  changes 
in  the  kidneys  develop  in  primary  circulatory  disorders. 

The  edema  of  cardiac  failure  arises  chiefly  from  circulatory  factors 
leading  to  increased  reabsorption  of  sodium  and  water  in  the  distal 
tubules'"".  Nevertheless,  venous  stasis  augments  the  capillary  pressure 
and  explains  some  of  the  accumulation  of  fluid;  low  concentrations  of 
albumin  in  serum  may  develop  and  have  a  similar  effect.  It  is  not  known 
whether  the  tubular  absorption  is  increased  owing  to  high  venous  pres- 
sure in  the  kidneys,  to  decrease  in  the  rate  of  glomerular  flltration,  to 
hormonal  influences  or  to  a  combination  of  these  factors.  In  any  case 
there  is  no  permanent  renal  damage,  since  the  kidneys  respond  normally 
when  the  circulation  is  improved.  Other  types  of  circulatory  failure 
probably  lead  to  disturbances  in  renal  circulation  which  invoke  reten- 
tion of  water  and  electrolyte.  Decrease  in  the  effective  plasma  volume 
is  an  important  factor  leading  to  increased  reabsorption  of  sodium  and 
water  by  the  kidneys,  since  the  following  conditions  are  associated  with 
this  phenomenon:  hypoproteinemic  states  with  or  without  renal  disease, 
hemorrhage,  shock,  dehydration,  exercise,  assumption  of  the  posture 
and  certain  liver  diseases. 

The  effect  of  mercurial  and  certain  other  diuretics  has  been  thought 
to  depend  on  decrease  in  the  reabsorption  of  sodium  in  the  distal 
tubules.  \A'illiam  Wallace  and  associates  have  unpublished  data  which 
throw  light  on  certain  features  of  the  diuresis.  In  many  patients  chloride 
is  lost  in  excess  of  sodium  so  that  alkalosis  develops.  \\'hen  this  occurs, 
mercurial  diuretics  are  likely  not  to  produce  further  loss  of  body  fluids. 
Other  patients  lose  sodium  and  chloride  in  the  proportions  found  in 
extracellular  fluids  and  are  likely  to  show  continuous  diuretic  response. 
Restoration  of  chloride  concentration  by  ammonium  chloride  usually 
restores  the  diuretic  response  in  the  patients  developing  alkalosis.  Al- 
though some  of  the  patients  de\'cloping  alkalosis  lose  body  potassium, 
the  losses  are  not  great,  and  they  do  not  develop  in  all  cases.  Apparently 
the  mercurial  diuretics  produce  a  disturbance  in  renal  function  leading 
to  relative  chloride  deficits  with  a  minimal  tendency  to  potassium  loss. 
In  this  type  of  alkalosis  potassium  chloride  is  hardly  indicated,  since  the 
diet  contains  abundant  potassium,  and  deficit  of  chloride  is  the  chief 
cause  of  the  alkalosis. 

Edema  is  a  prominent  feature  of  a  number  of  different  types  of  renal 

diseases  such  as  acute  hemorrhagic  nephritis,  nephrosis  and  some  types 

of  chronic  nephritis.    In  acute  hemorrhagic  nephritis  increase  in  the 

permeability  of  the  capillaries  to  proteins  plays  a  role  in  the  develop- 

Voi..  I.  152 


ABNORiMAL  LOSSES  OF  \VA  lER  AND  ELECl  ROLY  IE    983 

luent  of  cdcniii.  In  other  types  of  renal  diseases  cardiac  failure  occurs. 
In  most  types  of  marked  edema  regarded  as  primarily  nephrogenic,  low 
concentration  of  serum  albumin  develops.  It  is  a  frequent  observation 
that  diuresis  occurs  without  restoration  of  the  concentration  of  senuii 
albumin.  Nevertheless,  diuresis  nray  be  quite  regularly  induced  by  the 
repeated  injection  of  puriried  plasma  albumin.  While  this  procedure 
usually  raises  the  serum  albumin  concentration,  it  has  not  been  proved 
that  the  diuretic  effect  is  merely  a  result  of  mobilizing  water  and  elec- 
trolytes from  the  interstitial  fluids.  The  diuresis  may  be  a  response  of 
the  tubular  cells  to  the  increase  in  plasma  volume  and  other  factors 
involving  the  general  circulation. 

Coller  and  associates""  ""  point  out  that  for  one  to  three  days  after 
major  operations  the  kidneys  fail  to  excrete  sodium  chloride  in  normal 
amounts,  if  salt  is  given,  and  fail  to  have  a  water  diuresis  in  response  to 
a  load  of  intravenous  glucose  solution.  After  operations  the  urine 
volume  is  low.  Administration  of  salt  solution  alone  may  produce  high 
serum  electrolyte  concentrations  or  edema.  Injections  of  large  amounts 
of  jrlucose  solution  may  reduce  serum  electrolyte  concentrations.  Un- 
less" there  is  shock,  which  leads  to  obligatory  expansion  of  interstitial 
fluids,  or  there  are  deficits  of  extracellular  water  and  electrolytes,  post- 
operative patients  need  but  small  amounts  of  water  and  electrolyte. 
Every  effort  should  be  made  to  prevent  shock  during  operations  by 
transfusicn  which  replaces  the  blood  losses,  but  if  shock  develops, 
additional  transfusions  should  be  given'"'.  Since  deficit  of  extracellular 
electrolytes  increases  the  susceptibility  to  shock,  water  and  electrolyte 
deficits  must  be  replaced  before  operations  as  well  as  after  operations, 
if  electrolyte  losses  are  occurring. 

Van  Slyke^"^  has  discussed  the  disturbances  in  renal  function  result- 
ing from  shock.  The  immediate  effect  is  oliguria  or  anuria.  \\'ith  de- 
crease in  the  effective  circulating  volume,  peripheral  vascular  constric- 
tion may  restore  urine  flow,  if  the  blood  volume  is  not  too  low.  If  the 
shock  is  severe,  the  kidney  may  be  included  in  the  peripheral  vascular 
constriction,  and  oliguria  may  result  despite  the  maintenance  of  a  blood 
pressure  as  high  as  100  mm  of  mercury.  If  renal  blood  flow  does  not 
remain  low  too  long,  restoration  of  blood  volume  will  be  followed  by 
rapid  recovery.  How^ever,  prolonged  anoxia  may  produce  renal  dam- 
age which  is  particularly  prominent  in  the  loop  of  Henle  and  the  distal 
renal  tubules.  These  tubules  seem  to  become  indifferent  to  water  and 
electrolytes,  and  anuria  results  from  the  reabsorption  of  practically  all 
the  glolnerular  flltrate.    Anuria  and  marked  oliguria  following  shock 

Vol.  I.  152 


984    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

may  lead  to  death  in  2  to  20  days.  Although  the  lesions  may  produce 
anuria  or  marked  oliguria  for  several  days,  regeneration  and  recovery 
often  occur.  In  many  cases  the  recovery  will  leave  permanent  renal 
damage  which  still  is  compatible  with  life^"'. 

The  treatment  of  renal  disturbances  accompanying  shock  should 
shorten  the  period  of  renal  anoxia  by  prompt  transfusions  of  blood  and 
replacement  of  deficits  of  water  and  electrolyte  if  they  are  present. 
When  the  oliguria  is  prolonged,  recovery  is  most  likely,  if  body  water 
and  the  concentrations  of  electrolyte  in  body  fluids  are  kept  as  nearly 
normal  as  possible^"^  This  end  can  be  attained  by  initial  administration 
of  appropriate  amounts  of  water,  sodium  chloride  and  sodium  bicar- 
bonate to  restore  body  fluids.  Blood  volume  may  have  to  be  sustained 
by  transfusions.  During  prolonged  oliguria  sufficient  water  must  be 
supplied  from  day  to  day  to  replace  the  obligatory  expenditure  which 
will  be  low  owins^  to  failure  of  urine  formation.  One  must  avoid  giving 
enough  water  to  decrease  the  concentration  of  plasma  electrolyte  or 
enough  sodium  chloride  to  expand  greatly  extracellular  fluids.  The 
therapeutic  program  should  be  controlled  so  that  body  weight  remains 
relatively  constant,  while  enough  water  and  electrolyte  are  given  to 
keep  electrolyte  concentrations  normal  as  determined  by  frequent 
analyses  of  the  serum.  High  water  intakes  will  not  increase  urinary 
volumes  in  this  type  of  intrinsic  renal  damage.  Furthermore,  low  serum 
electrolyte  concentrations  may  produce  general  circulatory  disturb- 
ances which  interfere  with  renal  recovery.  The  opinion  that  water  is 
effective  in  oliguria  arises  from  the  fact  that  one  kind  of  oliguria  is 
produced  by  deficits  of  water  and  electrolytes  and  is  treated  eff^ectively 
by  replacing  the  deficits.  The  fluids  may  be  given  by  mouth,  if  there 
is  no  nausea  or  vomiting,  but  intravenous  therapy  usually  is  necessary 
in  severe  cases.  Diets  may  be  given  if  they  do  not  induce  vomiting  or 
nausea.  They  should  contain  practically  no  protein  or  potassium.  Suffi- 
cient glucose  or  carbohydrate  should  be  given  each  day  to  provide 
maximal  protein  sparing.  This  will  decrease  the  rate  of  release  of  potas- 
sium from  the  katabolism  of  tissues.  Since  proteins  and  amino  acids 
accelerate  the  final  toxic  reaction,  they  are  contraindicated. 

During  convalescence  from  oliguria  the  urine  is  likely  to  be  low 
in  concentration.  In  some  cases  sodium  will  be  poorly  reabsorbed,  but 
after  some  disturbances  recovery  of  sodium  reabsor}:)tion  may  occur, 
while  failure  of  reabsorption  of  water  persists^""'  '"^  Since  some  of  these 
patients  have  had  cerebral  symptoms,  it  is  possible  that  there  is  injury 
to  the  neurohypophysis  which  leads  to  deficient  production  of  the 

Vol.  I.  152 


ABNORiMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    985 

antidiuretic  homionc.  At  least  in  some  of  these  patients  increased  serum 
electrolyte  concentration  has  occurred  on  normal  salt  intakes.  Some 
patients  with  calcification  of  the  renal  tubules  show  hyposthenuria  with 
high  concentrations  of  sodium  and  chloride  in  the  serum'"'  '"''.  Treat- 
ment must  consider  these  possibilities. 

Therapy  of  renal  disturbances  is  based  on  the  calculation  of  the 
rate  of  water  and  electrolyte  expenditure  and  the  changes  in  body  com- 
position that  the  losses  of  water  and  electrolytes  have  produced.  Deter- 
minations of  the  serum  electrolyte  concentrations  usually  are  necessary, 
but  these  do  not  accurately  reveal  the  intracellular  changes.  When  the 
urinary  specific  gravity  is  fixed  at  1.012,  about  85  ml  of  water  is  re- 
quired to  excrete  the  load  created  by  metabolizing  100  calories.  This 
indicates  that  the  water  intake  may  have  to  be  as  high  as  150  ml  per  100 
calories  metabolized.  The  load  may  be  reduced  by  diets  low  in  protein, 
but  protein  should  not  be  lower  than  that  which  will  support  good 
nutrition.  As  was  indicated,  salt  may  have  to  be  added,  if  it  is  wasted, 
but  in  consideration  of  the  eifect  of  high  intakes  of  sodium  on  the 
blood  pressure  and  the  fomiation  of  edema,  salt  is  given  with  caution. 

Finally  in  considering  the  factors  controlling  the  expenditure  of 
water  and  electrolyte,  it  is  necessary  to  point  out  that  the  shifts  of  water 
and  electrolyte  within  the  body  change  the  amount  that  is  available  for 
expenditure.  If  there  is  increase  in  extracellular  fluids  owing  to  the 
formation  of  edema  or  exudates,  sufficient  water  and  electrolyte  must 
be  retained  to  maintain  the  concentrations  of  extracellular  fluids.  When 
such  fluids  are  excreted,  a  corresponding  amount  of  water  and  electro- 
lyte is  released.  These  facts  must  be  borne  in  mind  in  estimating  the 
requirement  of  water  and  electrolyte. 

There  is  such  a  small  amount  of  water  and  electrolyte  in  the  body 
that  can  be  safely  used  for  the  obligatory  expenditure  that  small  losses 
produce  symptoms  of  dehydration.  The  dangers  of  dehydration  have 
been  sufficiently  emphasized  so  that  physicians  do  not  knowingly  call 
on  body  water  to  cover  obligatory  expenditure.  It  is  not  so  generally 
realized  that  expansion  of  body  fluids  may  leave  the  rest  of  the  body 
with  insufficient  water  and  electrolyte  for  the  renal  and  circulatory 
systems  to  function  properly.  Burns,  exposure  to  cold,  extensive  trauma, 
inflammatory  reactions  and  injury  due  to  ischaemia  produce  large 
expansions  of  fluids  at  the  site  of  the  injury.  The  fluid  accumulated 
resembles  extracellular  fluids,  and  the  localization  of  the  water  and 
electrolyte  has  the  same  eff^ect  as  loss  of  extracellular  water  and  elec- 
trolyte'". 

Vol.  I.  152 


(VirtR  1 3  .52 


986    REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

Accompanying  the  circulatory  changes  of  tissue  injury,  potassium 
may  be  released  from  the  cells  and  replaced  by  sodium'".  The  decrease 
in  extracellular  sodium  produces  acidosis  which  is  further  aggravated 
by  changes  in  renal  function  dependent  on  the  lack  of  water  and  elec- 
trolyte for  the  renal  and  circulatory  systems.  Part  of  the  benefit  of  salt 
therapy  in  shock  is  dependent  on  these  changes  in  the  cells  and  the 
obligatory  expansion  of  extracellular  fluids. 

Specific  ion  effects  from  the  changes  in  concentration  of  sodium  and 
chloride  are  not  recognized  except  that  alkalosis  may  produce  or  ag- 
gravate tetany.  However,  certain  disturbances  develop  which  are 
attributed  to  low  or  hig^h  concentrations  of  potassium  in  plasma. 


Hypokiiliev/ict 

The  following  signs  and  symptoms  have  been  observed  when  the 
serum  potassium  concentrations  are  low:  (i)  weakness  and  hypotonia 
of  the  skeletal  muscles  progressing  to  frank  paralysis,  ( 2 )  dyspnea  with 
a  gasping  type  of  respirations  in  which  the  accessory  muscles  of  respira- 
tion are  invoked,  (3)  cyanosis  which  usually  is  respiratory  but  may  be 
cardiac,  (4)  abdominal  distention  which  probably  is  dependent  on 
atonia  of  the  smooth  muscle;  in  experimental  animals  and  probably  in 
patients  extreme  deficiency  of  potassium  may  produce  paralytic  ileus, 
(5)  nausea  and  vomiting,  (6)  cardiac  enlargement  with  the  appearance 
of  systolic  murmurs,  (7)  increased  pulse  pressure  with  Corrigan  pulse, 
(8)  elevated  venous  pressure  and  sis^ns  of  cardiac  failure.  The  paralysis 
of  the  diaphragm  and  the  abdominal  muscles  and  the  functional  disturb- 
ances in  the  myocardium  account  for  the  major  clinical  signs  and  symp- 
toms.   The  electrocardiographic  changes  are  described  later. 

Physiologically  significant  decrease  in  the  concentration  of  potas- 
sium in  serum  may  occur  without  characteristic  signs  and  symptoms. 
Nevertheless,  most  of  the  symptoms  just  mentioned  occur  chiefly  when 
the  serum  concentration  is  low.  However,  while  the  serum  concentra- 
tion is  likely  to  be  low  when  there  is  deflciency  of  potassium  in  the  cells, 
if  there  is  abundant  water  available  and  the  circulation  is  adequate,  large 
deficiencies  in  the  cells  occur  when  the  circulation  is  poor  and  the  serum 
concentrations  of  potassium  are  normal  or  high.  For  this  reason  the 
specific  signs  and  low  serum  potassium  concentrations  will  enable  the 
physician  to  recognize  only  a  minority  of  the  cases  of  potassium  defi- 
ciency. 

Vol.  I.  152 


ABNORMAL  LOSSES  OF  WATER  AND  ELECTROLYTE    987 

HyperkiiJievjia 

The  following  signs  and  symptoms  have  been  recognized  in  hvper- 
kaliemia:  (i)  Hstlessness  and  mental  confusion,  (2)  numbness  and  tin- 
gling of  the  hands  and  feet  with  a  sense  of  weakness  and  heaviness  of 
the  legs,  (3)  cold  gray  pallor,  (4)  bradycardia  and  occasionally,  totally 
irregular  rhythm,  (5)  peripheral  vascular  collapse  with  diminished 
heart  sounds  and  low  blood  pressure,  (6)  in  a  few  uremic  patients  a 
rapidly  ascending,  flaccid  paralysis  with  less  involvement  of  the  trunk, 
head  and  bladder  than  the  arms  and  legs  and  (7)  cardiac  arrest. 

Electrocardio^raiiis  m  Hypo-  aud  Hyper-kalieviia 

There  are  progressive  changes  in  the  electrogram  which  correlate 
roughly  with  the  concentration  of  potassium  in  the  serum.  These  are 
illustrated  diagrammatically  in  chart  VIL  When  the  concentration  of 
potassium  is  low  (below  3  mAl  per  liter),  the  following  alterations  have 
been  noticed:  (i)  slightly  prolonged  QT  interval,  (2)  decrease  in  the 
height  and  inversion  of  the  T  waves,  (3)  rounded  and  prolonged  T 
waves  which  may  nm  into  the  P  waves,  (4)  depression  of  the  ST  seg- 
ment and  (5)  possibly,  inversion  of  the  P  waves,  extrasystoles  and  AV 
block.  The  precordial  lead  CR3  has  been  the  most  useful  in  measuring 
the  QT  interval.  The  height  of  the  T  waves  has  been  found  to  be 
influenced  by  the  pH,  partial  carbon  dioxide  pressure  and  the  concen- 
tration of  potassium.  The  changes  in  the  electrocardiogram  are  reversed 
by  restoration  of  the  concentration  of  potassium  in  serum  when  low 
concentration  of  this  ion  is  the  cause  of  the  change""'  "^'  "-. 

The  changes  in  the  electrocardiogram  accompanying  elevation  of 
the  concentration  of  potassium  in  serum  are  fairly  characteristic.  The 
T  waves  may  become  elevated  and  peaked  at  concentration  of  potas- 
sium in  serum  as  low  as  6.5  to  7.8  mM  per  liter.  These  changes  are 
present  invariably  at  concentrations  greater  than  8  mM  per  liter.  In- 
crease in  the  duration  of  the  QRS  complex  develops  after  the  change 
in  the  T  waves.  Increased  duration  of  the  PR  interval,  leading  to 
auricular  standstill,  then  develops.  Totally  irregular  rhythm  and  heart 
block  develop  at  concentrations  of  10  mM  per  liter  or  slightly  more"  ■'•' 

Vol.  I.  152 


m^A  1  3  -52 


988     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

Summary 

The  purpose  of  this  chapter  is  to  present  the  physiological  basis  for 
fluid  therapy.   The  chief  factors  to  be  considered  are:   (i)  the  changes 


SERUM    K 
M  M  PER  L 


LOW 


NORMAL 
3.5-6 


HIGH 
I 

7 


t 
10 


i 


INVERTED  T 
DEPRESSED  ST 
PROLONGED   QT 

LOW  WIDE      T 
LONG  QT 

LOW  VOLTAGE 


-[NORMAL 


m^\mJ  \my\i    "C^L 


'N.-Ay*^  -f 


EVATED    T 


LONG  PR 

WIDE  QRS 

LLOW  ST 


-  ABSE  NT      P 


-[  Bl  PHASIC 


ECG    WITH      CHANGING     SERUM      K 


Chart  \^II.    Diagrams  of  electrocardiogram  with  changing  concentration  of  serum 
potassium. 

in  tissue  composition  and   (2)   the  rate  of  expenditure  of  water  and 
electrolytes.   The  knowledge  of  these  factors  must  be  applied  with  due 
Vol.  I.  152 


SUMMARY  989 

respect  to  the  limitations  imposed  by  the  metabolic  disturbances  of  the 
particular  disease.  Only  the  general  principles  will  be  outlined  in  the 
following  paragraphs.  The  aim  of  fluid  therapy  is  the  restoration  and 
maintenance  of  normal  composition  of  the  body,  particularly  with 
respect  to  water  and  electrolytes. 

AMien  there  is  no  nausea  and  vomiting,  and  when  oral  fluids  do  not 
seriously  aggravate  the  losses  of  fluid  from  the  gastrointestinal  tract, 
the  oral  administration  of  fluid  or  food  is  the  method  of  choice.  If  one 
is  attempting  to  restore  electrolyte  by  mouth,  the  concentrations  of  the 
fluids  given  seldom  should  be  greater  than  one  third  physiological 
strength.  Concentrated  salt  solutions  are  likely  to  produce  nausea, 
vomiting  or  diarrhea  and  do  not  supply  enough  water  without  electro- 
lyte to  cover  the  obligatory  expenditure  as  insensible  water  and  as 
water  required  for  urine  formation.  The  various  required  ions  may  be 
added  to  beverages  or  food.  The  usual  intake  of  potassium  for  an  adult 
on  a  full  diet  is  4  grams  of  potassium  or  the  equivalent  of  about  8  grams 
of  KCl.  7  his  amount  may  be  safely  given  orally  and  usually  suffices 
to  replace  deficits  of  this  ion.  However,  more  may  be  given,  since  it  is 
difficult  to  induce  potassium  intoxication  by  potassium  taken  orally, 
except  \\hen  renal  excretion  is  limited  owing  to  adrenal  insufficiency, 
renal  disease  or  circulatory  failure.  Children  and  babies  may  be  given 
corresponding  amounts  but  dosage  should  be  based  on  the  relative 
caloric  production  rather  than  the  relative  weight.  The  usual  diets 
provide  enough  electrolyte  unless  there  are  large  deficits  or  unusual 
losses. 

Parenteral  therapy  is  required  when  large  deficits  must  be  replaced 
or  fluid  cannot  be  taken  orally.  Electrolyte  solutions  containing  chiefly 
sodium  at  physiological  concentrations  are  well  tolerated  subcutane- 
ously.  For  slow  intravenous  injection  the  fluids  may  be  about  three 
time  physiological  strength.  However,  solutions  more  concentrated 
than  physiological  saline  should  not  be  used  except  when  it  is  desirable 
to  raise  the  serum  concentrations.  As  the  sole  source  of  water,  physio- 
logical saline  and  other  similar  solutions  do  not  provide  enough  water 
free  of  electrolyte.  When  all  fluids  are  given  parenterally,  the  electro- 
lyte concentration  in  the  mixture  given  over  24  hours  should  seldom  be 
greater  than  one  third  physiological  saline.  Usually  the  total  require- 
ment of  water  and  electrolytes  for  twenty-four  hours  is  estimated  and 
added  to  5  or  10  per  cent,  solution  of  glucose.  Such  a  mixture  may  be 
injected  slowly  into  a  vein.   If  the  solution  is  injected  slowly,  and  the 

Vol.  I.  152 


fti^A  1  o  '52 


990     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

amount   of  glucose   does   not   provide   more   calories   than   are   being 
burned,  there  is  little  glycosuria. 

Certain  useful  solutions  for  parenteral  therapy  are  listed  in  Table  L 
They  are  classified  according  to  the  chief  metabolic  need  which  they 
meet.   The  preferred  method  of  administration  is  indicated  by  +  while 

TABLE  I 

Selected  List  of  Fluids  Used  in  Parenteral  Fluid  Therapy 

Contents  per  Liter  Daily  Dose 

^  I  Chief 

Glu-i  g  _ji   §  per     per  loo         Use* 

CI     Nil       K       P     cose  ~  5  c^  1  ^g'"    '■''/■  '""■'f- 

in.M  inM  n/M  in.\i  gin.  ""  '""  .^  cc.           cc. 

Appropriate  for   M^ater  Expenditure 

Glucose     o  o      o      o       50       +  (  +  )  So- 1:0         Nutrition 

Glucose     o  o      o      0100       +  80-120        Nutrition 

Appropriate  for  Na  and  CI  replacement 

Saline      154       154       o      o        o       -f  +       20-80  Alkalosis 

1/7   Al.Na  Lactate         014:500        o-f-  -j-       20-60  Acidosis 

Na  Lactate  Na  CI     loi        148       o       o        o-f  -|-       20-80  Acidosis 

Al.  Na  Lactate   ..         o     1000      000     (-|-)  4-8  Acidosis 

3.75%  NaHCO.5    .  o         45       o       o         o       -)-  Acidosis 

Appropriate  for  Na,  CI  and  K  replaceinetit 

Darrow    104       120     36      o        o     (  +  )  +       20-80  Acidosis 

Hutler   Talbot    ...       22         30     15       5       50       -\-  100-150        Acidosis 

Hutlcr  Talbot    ...       22         30     15       5     100       -f  100-150        Acidosis 

NaCl    KCl    137       102     36      o        o     (  +  )  +       20-80  Alkalosis 

Appropriate  for  Parenteral  Feeding 
H\drolvsate  of 
Caseine    33        50      7     29      50       +  (-f)  25-50  Nutrition 

Appropriate  for  Sl.vjck 
Whole   Blood    ...       32         80      4  +  5-30  Shock 

Plasma   80       200     10  -|-  5-40  Shock 

*  All  solutions  are  used  to  replace  water  and  provide  for  expenditure  according  to 
the  categories  indicated  in  the  table. 

(  +  )  indicates  that  the  solution  should  be  modified  by  dilution  or  that 
there  are  serious  drawbacks  to  this  method  of  administration.  The  sub- 
cutaneous injection  of  5  per  cent,  solution  of  glucose  is  irritating  locally 
and  immobilizes  water  and  electrolyte  for  several  hours.  A  mi.xture  of 
one  part  5  per  cent,  glucose  and  one  part  physiological  saline  or  equiva- 
VoL.  I.  152 


SUMMARY  991 

lent  has  few  of  these  objections.  Molar  sodium  lactate  should  be  diluted 
to  one  seventh  molar,  if  injected  subcutaneously,  or  to  less  than  one 
third  molar,  if  injected  intravenously.  The  solutions  containing  potas- 
sium that  are  desiirned  for  subcutaneous  administration  ( Harrow's  solu- 
tion or  the  mixture  of  NaCl  and  KCl)  should  be  diluted  one  part  to  2 
or  3  parts  of  5  or  10  per  cent,  glucose  if  injected  intravenously.  While 
solutions  of  amino  acids  or  proteins  hydrolysates  have  been  injected 
subcutaneously  in  a  3  per  cent,  solution,  they  are  irritating  locally. 

The  table  shows  the  analysis  of  one  type  of  enzyme  hydrolysate  of 
caseine  and  these  values  do  not  apply  to  other  preparations.  Solutions 
are  available  that  contain  practically  no  sodium  and  potassium.  If  the 
electrolyte  content  is  critical,  the  "analysis  of  the  particular  solution 
used  should  be  consulted.  Only  the  electrolyte  content  of  the  plasma 
was  estimated  in  the  case  of  whole  blood,  since  the  electrolyte  of  the 
cells  is  not  immediately  available  to  the  body  as  a  whole. 

TABLE  II 

Suitable  Maintenance  Requirements  per   100  Calories  Metabolized 

Protein 
Amino 
H  ,0  Acids      Glucose  NaCI  KCl 

2.C  22  0.06-0.12  0.07-0.14 


Gni 90-150 

mAI 


1-2 


Table  II  shows  the  estimated  requirements,  when  all  fluids  must  be 
administered  parenterally,  and  when  there  are  no  abnormal  losses  and 
no  unusual  amount  of  sweat.  Under  these  circumstances  the  expendi- 
ture of  sodium,  potassium  and  chloride  is  small,  and  the  fluids  adminis- 
tered should  not  contain  more  than  about  10  ml  of  physiological  saline. 
Twenty  nil  per  100  calories  metabolized  of  a  mixture  of  equal  parts 
physiological  saline  and  isotonic  potassium  chloride  (4.5  gm.  NaCl  and 
5.5  Q;m.  KCl  per  liter)  meets  the  expenditure  of  Na,  K  and  CI.  It  will 
be  seen  that  the  caloric  requirement  cannot  be  supplied  except  by 
injecting  about  150  ml  of  15  per  cent,  glucose  or  220  ml  of  10  per  cent, 
solution.  A  fifteen  per  cent  solution  is  irritating  to  the  veins  and  may 
produce  thrombosis.  Two  hundred  and  twenty  ml  per  100  calories  is 
a  high  fluid  intake,  and  while  it  may  be  used,  it  is  seldom  desirable. 
Fortunately  it  is  seldom  necessary  to  prescribe  full  calories,  since  the 
consumption  of  a  moderate  amount  of  tissue  fat  is  of  little  moment 
except  that  it  delays  the  recovery  of  body  protein.  The  use  of  homog- 
VoL.  1.  152 


nnti    lO.c-, 


992     REGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

enized  suspensions  of  fat  is  being  carried  out  successfully  but  still  is 
experimental.  If  the  use  of  intravenous  fat  becomes  generally  available, 
complete  parenteral  feeding  will  be  theoretically  possible.  It  is  usually 
advisable  to  add  one  of  the  intravenous  preparations  of  vitamins  when 
prolonged  parenteral  therapy  is  being  carried  out. 

In  most  examples  of  severe  dehydration,  shock  is  likely  to  develop. 
The  circulatory  failure  accompanying  loss  of  extracellular  water  and 
electrolytes  is  treated  most  effectively  bv  replacing  these  deficits,  but 
transfusions  of  blood  and  to  a  lesser  extent,  plasma,  improve  the  results. 
When  potassium  solutions  are  going  to  be  given  to  patients  suffering 
from  severe  dehydration  or  shock,  it  is  important  to  start  the  treatment 
with  the  intravenous  injection  of  lo  to  20  ml  of  saline  or  a  mixture  of 
sodium  chloride  and  sodium  lactate.  This  procedure  is  indicated,  be- 
cause the  concentration  of  potassium  in  serum  is  likely  to  be  slightly 
high  despite  a  large  intracellular  deficit  of  potassium.  Salt  solutions  will 
improve  the  circulation  and  renal  function  so  as  to  min-mize  the  dangers 
of  potassium  intoxication.  However,  it  is  seldom  necessary  to  delay 
the  injection  of  the  solution  containing  potassium  more  than  an  hour. 
Since  the  potassium-containing  solution  is  injected  slowly,  the  rate  can 
be  diminished,  if  renal  function  remains  impaired. 

In  the  authors'  experience  it  is  seldom  necessary  in  severe  acidosis 
due  to  infantile  diarrhea  to  give  more  sodium  bicarbonate  or  lactate 
than  is  contained  in  Darrow's  solution.  Since  this  condition  is  accom- 
panied by  as  great  losses  of  electrolyte  as  are  met  in  any  other  conditions, 
this  solution  should  be  equally  effective  in  other  types  of  severe  acidosis 
due  to  electrolyte  depletion.  If  it  seems  necessary  to  give  sodium  bicar- 
bonate or  lactate,  the  dose  is  indicated  in  the  table.  It  should  be  remem- 
bered that  acidosis  usually  is  accompanied  by  deficits  of  potassium  as 
well  as  sodium  and  that  the  administration  of  potassium  makes  it  unnec- 
essary to  give  large  doses  of  sodium  bicarbonate  to  restore  the  serum 
concentrations  of  bicarbonate. 

The  deficits  of  extracellular  electrolyte  are  unlikely  to  be  greater 
than  one  third  of  the  normal  extracellular  contents  or  9  miM  of  chloride 
or  1 2  mM  of  sodium  per  kilogram  of  body  weight.  The  deficit  of  these 
ions  may  be  replaced  rapidly  by  intravenous  or  subcutaneous  injections. 
The  deficit  of  potassium  is  unlikely  to  be  greater  than  17  miM  per 
kilogram  of  body  w  eight.  This  deficit  cannot  be  restored  rapidly  be- 
cause the  injection  of  potassium  at  a  rapid  rate  and  in  too  large  amounts 
may  produce  potassium  intoxication.  Furthermore,  the  cells  do  not 
seem  to  be  able  to  repair  the  deficiency  of  intracellular  potassium  very 

Vol.  I.  152 


SUMMARY  993 

rapidly.  The  nuthors  believe  that  the  optimal  dose  that  is  safe  and 
efficiently  utilized  is  3  niM  of  potassium  (0.22  gms.  of  KCl)  per  kilo- 
gram per  day.  One  to  two  mEq  of  potassium  per  kilogram  per  day 
usually  is  sufficient  to  produce  potassium  retention  and  prevent  serious 
decrease  in  serum  potassium  concentration.  The  injection  of  the  dose 
for  one  day  should  be  at  a  rate  that  requires  4  hours  or  more  for  the 
total  amount  since  this  assures  that  there  is  time  for  equal  distribution 
of  potassium  throughout  body  fluids.  When  there  is  oliguria  owing 
to  shock  or  dehydration,  the  concentration  of  potassium  in  serum  may 
be  high.  In  order  to  minimize  the  dangers  of  potassium  intoxication, 
intravenous  injection  of  about  20  ml  per  kilogram  of  a  solution  con- 
taining sodium  chloride  or  sodium  chloride  and  sodium  lactate  at  physi- 
ological strength  should  precede  the  use  of  solutions  containing  potas- 
sium. This  will  improve  the  circulation  and  start  renal  excretion  so  that 
it  is  safe  to  inject  the  solution  containing  potassium.  This  procedure 
need  not  delay  starting  the  potassium  therapy  by  more  than  an  hour. 
In  cases  with  his^h  electrolyte  concentrations  in  serum  it  is  advisable  to 
use  a  salt  mixture  diluted  about  half  with  5  per  cent,  glucose  or  only 
5  per  cent,  glucose.  It  usually  takes  4  to  6  days  to  replace  a  large  deficit 
of  potassium. 

In  alkalosis  physiological  saline  is  efl^ective  unless  there  are  large 
deficits  of  potassium.  Theoretically  the  mixture  of  sodium  and  potas- 
sium chloride  is  more  appropriate  in  most  cases  and  has  been  proved  to 
be  more  effective  in  cases  of  alkalosis  resulting  from  prolonged  vomiting 
or  as  a  result  of  post-operative  suction. 

The  treatment  of  marked  oliguria  and  anuria  as  a  result  of  intrinsic 
renal  disease  was  discussed  briefly  in  connection  with  shock.  Coller  and 
associates  have  pointed  out  that,  for  i  to  3  days  after  operations,  the 
kidneys  fail  to  respond  to  certain  renal  loads  that  have  been  a  part  of 
post-operative  care  in  many  hospitals.  The  kidneys  fail  to  excrete 
sodium  and  water  adequately.  For  this  reason  the  water  and  electrolyte 
expenditure  of  post-operative  patients  is  temporarily  low,  and  the  fluids 
prescribed  should  be  correspondingly  reduced.  However,  if  there  is 
shock  or  if  deficits  of  water  and  electrolyte  develop,  the  intake  of  salt 
solutions  should  be  higher.  The  best  method  of  treating  post-operative 
shock  is  by  transfusions,  preferably  by  giving  blood  at  the  time  of 
operations  according  to  the  blood  losses.  Since  patients  with  deficits 
of  water  and  electrolyte  do  not  withstand  operations  well,  such  defi- 
ciencies always  should  be  replaced  before  operations. 

Vol.  I.  152 


994    RFGULATION  OF  BODY  WATER  AND  ELECTROLYTE 

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January  i,  1952 


Vol.  I.  152 


MAR  13.52 


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